In recent decades, significant progress in medical science, particularly in critical care medicine, has markedly improved patient outcomes through novel theories and technologies. However, bloodstream infections (BSIs), especially those caused by Gram-negative bacteria (GNB), remain a formidable challenge due to their high incidence and mortality rates, imposing substantial healthcare and economic burdens globally (1–3). Recent epidemiological data reveal an upward trend in BSI incidence (4). Concurrently, the pathogen distribution has shifted: while methicillin-resistant Staphylococcus aureus (MRSA) prevalence has declined, multidrug-resistant Gram-negative bacteria (MDR-GNB) has become increasingly predominant. Currently, Escherichia coli is the leading BSI pathogen, with GNB accounting for over 50% of cases (4, 5). BSI-associated mortality remains alarmingly high, ranging from 10 to 20%, and exceeding 30% in elderly populations (4). These trends underscore the urgent need for optimized therapeutic strategies, enhanced diagnostic approaches, and robust infection control measures to mitigate the impact of BSIs.

The implementation of rational and effective antibiotic therapy is a critical strategy for improving the prognosis of patients diagnosed with BSI. Current research indicated that timely and appropriate antibiotic administration significantly enhances outcomes for patients with BSI and sepsis (6, 7). While the importance of early antibiotic initiation is well-established, the optimal duration of antibiotic therapy remains a subject of ongoing debate. For BSI, specifically short-term central venous catheter-related bloodstream infections (CRBSI), the Infectious Diseases Society of America (IDSA) (8) and the Spanish Society of Clinical Microbiology and Infectious Diseases (SEIMC) (9) provided expert consensus recommendations. According to these guidelines, following the removal of the central venous catheter (CVC), a treatment duration of 7 to 14 days was recommended for uncomplicated infections caused by GNB and enterococci (8, 9). However, the optimal duration of antimicrobial therapy for non-CRBSI remains unclear, as no definitive consensus exists. In summary, there is currently insufficient robust evidence to establish the optimal anti-infective treatment regimen for BSI. It is important to recognize that while appropriate antibiotic therapy improves patient outcomes, prolonged antibiotic exposure can increase the risk of adverse drug reactions and contribute to the development of antibiotic resistance (10, 11). Therefore, minimizing the duration of antibiotic therapy is essential to reduce the risk of resistance, decrease the incidence of adverse events, and alleviate the financial burden on healthcare systems.

Several prior meta-analyses have compared the efficacy and safety of long-course antibiotic treatment (>10 days) versus short-course treatment (≤10 days) for BSI. These studies have revealed that short-term and long-term treatment strategies yield similar clinical efficacy, and no statistically significant differences in adverse event rates were detected between the two approaches (12, 13). Another meta-analysis focusing specifically on Gram-negative bacteria bloodstream infections (GNB-BSI) demonstrated comparable efficacy and safety profiles between 7-day and 14-day antibiotic treatment regimens, with no statistically significant differences observed (14). The study population of the above-mentioned meta-analysis exclusively comprised patients diagnosed with uncomplicated GNB-BSI. A recently published randomized controlled trial (RCT), the largest of its kind to date, evaluated the efficacy and safety of 7-day versus 14-day antibiotic regimens for BSI management (15). The results demonstrated that a 7-day antibiotic regimen was non-inferior to a 14-day regimen in patients with BSI. This study contributes significant, high-quality evidence to inform the selection of appropriate antibiotic treatment durations for the management of BSI. In light of these findings, we performed an updated systematic review and meta-analysis specifically focusing on patients with uncomplicated BSI. This study comparatively evaluated the clinical outcomes of 7-day versus 14-day antibiotic regimens, with dual objectives: (1) to assess efficacy (all-cause mortality, 90-day mortality) and (2) to assess safety profiles (relapsed bacteremia, adverse events, etc.). Our findings provide contemporary, evidence-based guidance for antimicrobial stewardship in uncomplicated BSI management.

This updated meta-analysis incorporated data from the largest RCT to date, demonstrating no significant difference in all-cause mortality or 90-day mortality between 7-day and 14-day antibiotic treatment regimens for uncomplicated non-Staphylococcus aureus BSI, particularly in cases of GNB-BSI. Trial sequential analysis revealed that the current sample size has not yet reached the required information size, suggesting the possibility of false-negative results. These findings underscore the need for further large-scale RCTs to validate the conclusions. Regarding secondary outcomes, the 7-day antibiotic regimen was associated with a shorter length of stay in hospital compared to the 14-day regimen. However, no significant differences were observed in relapsed bacteremia, readmissions or prolongation of hospitalization, suppurative complications, emergence of resistance. In terms of adverse events, both groups exhibited comparable incidences of AKI, CDI, diarrhea, and rash.

The optimal duration of antibiotic therapy remains a critical issue in clinical practice. Prolonged antibiotic use was associated with an increased risk of adverse effects (10, 20–23) and the emergence of antibiotic-resistant pathogens (24–26). Conversely, insufficient treatment duration may compromise therapeutic efficacy (27, 28) and lead to higher healthcare costs. Therefore, it is essential to balance minimizing the duration of antibiotic therapy to the shortest effective period while ensuring therapeutic efficacy, reducing adverse events, mitigating antimicrobial resistance, and alleviating the economic burden on healthcare systems.

The optimal duration of antibiotic therapy for BSI has been extensively investigated. A meta-analysis conducted by Li et al. (12) demonstrated that in patients with GNB-BSI, no significant differences were observed in 30-day mortality, 30-day recurrent bacteremia, 90-day mortality, or adverse event rates between short-course (6 to 11 days) and long-course (>10 days) antibiotic treatments. Similarly, another meta-analysis (13) focusing on Enterobacteriaceae-induced BSI, which included five studies involving 2,865 patients, reported no statistically significant differences in 30-day all-cause mortality, 90-day all-cause mortality, or clinical cure rates between short-course (≤10 days) and long-course (>10 days) antibiotic regimens. Furthermore, a meta-analysis restricted to RCTs (14) revealed that for uncomplicated GNB-BSI, a 7-day antibiotic course yielded comparable outcomes to a 14-day course in terms of mortality, recurrent bacteremia, hospital length of stay, infectious complications, drug resistance, and adverse events. Despite variations in the definitions and durations of antibiotic therapy across these studies, consistent findings demonstrate that the benefits of short-course antibiotic treatment for patients with bloodstream infections are not significantly inferior to those of long-course therapy.

In the current meta-analysis, three RCTs specifically enrolled patients diagnosed with GNB-BSI. An additional RCT (BALANCE trial) excluded patients who had a positive culture with a common contaminant (such as coagulase-negative staphylococci), had Staphylococcus aureus or S. lugdunensis bacteremia, bacteremia from rare organisms that required prolonged receipt of treatment, or fungemia. This RCT primarily focused on BSI caused by GNB, while also including cases involving Gram-positive cocci such as enterococci. Among the total cohort of 3,608 patients, 625 (17.3%) were identified as having Gram-positive bacterial infections (15). The study demonstrated that the 7-day antibiotic regimen was non-inferior to the 14-day antibiotic regimen, and consistent outcomes were observed in subgroup analyses following the exclusion of Gram-positive bacterial infections. These studies collectively demonstrated the feasibility and safety of 7-day antibiotic regimen in specific patient populations. At the same time, The BALANCE trial employed a stringent non-inferiority margin (Δ = 4%) for 90-day mortality, which was notably more conservative than conventional NI thresholds, thereby strengthening the validity of its non-inferiority conclusions. Although the BALANCE trial contributed a substantial proportion (76%) of the total sample size, sensitivity analysis demonstrated consistent results, indicating that its inclusion did not compromise the robustness of our findings. Although the trial TSA results suggested potential false-negative conclusions with the current data, incorporating the BALANCE trial significantly enhanced statistical power through sample size expansion, thereby strengthening the reliability of our findings.

While our meta-analysis demonstrated comparable all-cause and 90-day mortality rates between 7-day and 14-day antibiotic regimens, we found a wide range of all-cause mortality rates reported between different studies (2.5 to 15%). As illustrated by the 15% mortality rate in the BALANCE trial (7-day group) versus the 2.5% rate reported by Molina et al. This discrepancy primarily reflects differences in baseline disease severity: the BALANCE trial enrolled more critically ill patients, with a mean Sequential Organ Failure Assessment (SOFA) score of approximately 5, compared to mean scores of 2 in Yahav et al.’s trial and a quick SOFA (qSOFA) score of about 1 in von Dach et al.’s study.

However, it is crucial to identify which patients are appropriate for a 7-day antibiotic regimen and which patients require a 14-day or extended course of therapy. First, based on the shared characteristics identified across the four studies, a 7-day treatment course may be sufficient for uncomplicated GNB-BSI. Specifically, this applies to patients with positive blood cultures who exhibit no endocarditis, no indwelling medical devices, no metastatic infectious foci, and resolution of fever within 72 h of treatment initiation. In such cases, extending the treatment duration to 14 days is unlikely to yield additional clinical benefits. Second, for patients demonstrating early clinical improvement, such as normalization of body temperature and reduction in inflammatory markers, a 7-day treatment course may represent a safe and effective option. However, patients with complicated bloodstream infections, such as those involving concomitant endocarditis, osteomyelitis, or deep abscesses, typically require an extended treatment duration of 4–6 weeks to ensure complete eradication of the infection (7, 8). As demonstrated in the study by Babe et al. (29), patients with blood culture-positive infective endocarditis exhibit significantly higher risks of severe complications, including heart failure (HF) and septic shock, with mortality rates approaching 30%. In addition to surgical intervention when indicated, these findings support the clinical rationale for extended antibiotic therapy in this high-risk patient population. On the other hand, Staphylococcus aureus infections are often more invasive, and prolonged antibiotic therapy is generally recommended for Staphylococcus aureus BSI to minimize the risk of recurrence. Previous studies (27) have demonstrated that in Gram-positive bacterial bloodstream infections, particularly Staphylococcus aureus bacteremia, shorter antibiotic courses are associated with an increased risk of recurrence. Furthermore, immunocompromised patients, including organ transplant recipients, those with chemotherapy-induced neutropenia, or individuals on long-term immunosuppressive therapy, may require individualized treatment adjustments due to their heightened susceptibility to infections and more complex clinical conditions.

Studies investigating infections at various sites, beyond BSI, have also demonstrated comparable efficacy and safety between short-course and long-course antibiotic therapy (28, 30, 31). This evidence prompts the question: is less more? Minimizing antibiotic exposure while maintaining therapeutic efficacy is highly desirable, as it reduces the risk of adverse events and mitigates the development of antimicrobial resistance. However, it is critical to emphasize that timely source control is a cornerstone of effective infection management and plays a pivotal role in reducing the necessity for prolonged antibiotic therapy. For instance, in cases of catheter-related bloodstream infections, removing the central venous catheter and administering antibiotics for 7 days or fewer has been shown to be as safe and effective as longer treatment durations (32). Similarly, for BSI secondary to various infectious sources—such as urinary tract infections, localized abscesses, pneumonia, and intra-abdominal infections—source control may be more impactful than the duration of antibiotic therapy (33–35). These findings highlight the importance of a targeted approach to infection management, emphasizing source control alongside judicious antibiotic use.

We performed a comparative analysis to assess the efficacy and safety of two antibiotic treatment durations (7-day versus 14-day courses) for BSI. However, the study was limited by the unavailability of raw data, which precluded subgroup analyses based on critical factors such as pathogen type and infection source. Furthermore, trial sequential analysis indicated the potential for a false-negative outcome, necessitating cautious interpretation of the meta-analysis results. A recent individual patient data (IPD) meta-analysis (36) on this topic primarily demonstrated the non-inferiority of 7-day antibiotic therapy compared to 14-day treatment. Although the four included studies overlap with our analysis, our meta-analysis provides distinct methodological rigor and novel insights that enhance the current evidence base, our study remains a critical component of the evidence-based assessment in this field. Furthermore, our findings provide additional insights by highlighting potential risks of false-negative conclusions from alternative analytical perspectives. Moving forward, the ongoing SHORTEN-2 trial (37), a large-scale RCT, aims to further evaluate the efficacy and safety of a 7-day versus a 14-day antibiotic regimen for Pseudomonas aeruginosa bloodstream infections. We will closely monitor the publication of its findings and promptly update our systematic review and meta-analysis to integrate these results. This will enhance the evidence base for determining the optimal duration of antibiotic therapy in BSI, ultimately supporting improved clinical decision-making and patient outcomes.

We systematically evaluated the efficacy and safety of a 7-day antibiotic regimen compared to a 14-day regimen for the treatment of BSI. This study represents the most comprehensive meta-analysis to date, both in terms of sample size and the number of RCTs included. Furthermore, trial sequential analysis was conducted to validate the robustness of our findings. Nevertheless, several limitations should be acknowledged. First, significant heterogeneity was observed in the inclusion and exclusion criteria across the included studies. For example, two studies enrolled patients with mixed Gram-negative bacterial infections, one study focused exclusively on Enterobacteriaceae infections, and another included patients with BSI caused by a wide range of pathogens, including Gram-positive bacteria. Second, variations in antibiotic prescriptions, particularly in empirical treatment regimens, may have introduced considerable variability, potentially affecting the reliability of the results. Third, the lack of subgroup analyses based on pathogen type, antibiotic resistance profiles, and specific infection sources limits our ability to evaluate the impact of these factors on outcomes. Fourth, although TSA was performed to assess the reliability of our conclusions, the results suggest a potential risk of Type II errors (false negatives), which may undermine the robustness of the meta-analysis findings. And these findings underscore the critical need for additional large-scale RCTs to robustly validate these conclusions. Finally, it should be emphasized that our study specifically evaluated patients with uncomplicated GNB-BSI. While our findings provide important insights for GN-BSI management, their generalizability to bloodstream infections caused by other pathogens (e.g., Gram-positive bacteria or fungi) may be limited.

Our systematic review and meta-analysis demonstrated that, for patients with BSI, a 7-day antibiotic regimen was associated with a shorter length of stay in hospital compared to a 14-day regimen. However, no significant differences were observed in mortality rates, relapsed bacteremia, readmissions or prolongation of hospitalization, suppurative complications, or the emergence of resistance. Similarly, both regimens showed comparable results in terms of adverse events. Trial sequential analysis suggested that the current findings may be subject to false-negative conclusions. Therefore, further high-quality RCTs with larger sample sizes are warranted to comprehensively evaluate the efficacy, safety, development of antibiotic resistance, and cost-effectiveness of 7-day versus 14-day regimens. Moreover, further high-quality studies are needed to explore the effects of varying antibiotic durations on different pathogens and to address the limitations identified in this analysis.