Comparing Long Versus Shorter Antibiotic Regimens for Gram-Negative Bacteremia and Their Implications in Antimicrobial Resistance: A Systematic Review And Meta-Analysis

Comparing Long Versus Shorter Antibiotic Regimens for Gram-Negative Bacteremia and Their Implications in Antimicrobial Resistance: A Systematic Review And Meta-Analysis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Systematic Review Comparing Long Versus Shorter Antibiotic Regimens for Gram-Negative Bacteremia and Their Implications in Antimicrobial Resistance: A Systematic Review And Meta-Analysis Shankar Biswas, Elangovan Krishnan, Urvashi Bharia, Harkirat Singh, and 14 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7613830/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background The optimal duration of antibiotic therapy for gram-negative bacteremia remains uncertain. We conducted a systematic review and meta-analysis to compare short (≤ 10 days) versus long (> 10 days) antibiotic duration for gram-negative bacteremia in hospitalized adults. Methods We searched MEDLINE, Embase, Cochrane Library, and trial registries from inception to June 2025. We included randomized controlled trials (RCTs) and observational studies comparing antibiotic durations for gram-negative bacteremia. Two reviewers independently screened studies, extracted data, and assessed risk of bias using RoB 2.0 for RCTs and Newcastle-Ottawa Scale for observational studies. Primary outcomes were 30-day mortality and relapse. Secondary outcomes included 90-day mortality, antibiotic-associated adverse events, and antimicrobial resistance (AMR). We calculated risk ratios (RR) with 95% confidence intervals (CI) using random-effects models and assessed certainty of evidence using GRADE. Results Seven studies (4 RCTs, 3 observational) including 4,520 patients met inclusion criteria. Short duration therapy showed no significant difference in 30-day mortality compared to long duration (87/1,185 [7.3%] vs 91/1,365 [6.7%]; RR 1.10, 95% CI 0.83–1.46; I²=5%; moderate certainty) or 30-day relapse (33/1,200 [2.8%] vs 53/1,378 [3.8%]; RR 0.85, 95% CI 0.55–1.32; I²=0%; moderate certainty). Four studies reporting 90-day mortality (including BALANCE trial gram-negative subgroup) showed no significant difference (328/2,272 [14.4%] vs 357/2,248 [15.9%]; RR 0.91, 95% CI 0.79–1.04; I²=40%; moderate certainty). Sensitivity analyses were consistent across study designs, study quality, and analytical approaches. Risk of bias was low for observational studies (Newcastle-Ottawa Score ≥ 8/9) and showed some concerns for RCTs due to open-label design. Conclusions Moderate certainty evidence suggests that short duration (≤ 10 days) antibiotic therapy is non-inferior to longer courses for gram-negative bacteremia, with no significant differences in mortality or relapse. These findings support shorter antibiotic courses to reduce antibiotic exposure while maintaining clinical effectiveness. Adverse events and AMR were infrequently reported. In light of recent fears of drug-resistant bacteria, future studies on the same are recommended. Infectious Diseases Short course Long course Gram-Negative bacteremia Mortality Relapse Antimicrobial resistance Figures Figure 1 Figure 2 Figure 3 Figure 4 INTRODUCTION Bloodstream infections (BSIs), particularly those attributed to gram-negative bacilli, continue to represent a substantial global public health challenge, directly correlating with high morbidity and mortality rates. ( 1 ) Longer antibiotic therapy durations risk increased nosocomial infections, and subsequent longer hospital stays; antibiotic adverse effects, and the potential emergence of antimicrobial drug resistance. ( 2 ) There is limited conclusive evidence indicating effective treatment duration of gram-negative bacteremia (GNB). Studies showed variable outcomes for duration ranging from 7 to 14 days or even longer based on patient conditions, clinician opinions and severity of BSI, hence the question on ideal duration persists. ( 3 – 10 ) Since the beginning of the 21st century, global antibiotic consumption has increased by 65%. An estimated 70 billion antibiotic doses are consumed annually.( 11 ) There is an alarmingly high level of broad-spectrum antibiotic over prescription for key conditions across primary care settings in India, China, and Kenya. ( 12 ) This phenomenon, coupled with the ever-increasing rates of antimicrobial resistance (AMR) worldwide, affect the clinical management of various diseases, including GNB. Reduction of antibiotic treatment duration to minimize consequences of antibiotic overuse, while simultaneously balancing clinical outcomes like treatment failure and recurrence with shortened regimens, is the need of the hour. ( 13 ) We conducted a systematic review and meta-analysis to evaluate the differences in treatment outcomes for greater than, versus less than 10 days of antimicrobial therapy in patients with uncomplicated GNB, with 30-day mortality outcomes as the primary outcome. METHODOLOGY Study Selection The systematic search across PubMed, Scopus, Embase, Clinicaltrial.gov , and Cochrane Library, identified 144 records from inception till June 2025. The search approach combined Medical Subject Headings (MeSH) terms and free-text keywords. The search terms included- ("gram-negative bacteremia" OR "bloodstream infection") AND ("7-day" OR "short course") AND ("10-day" OR "14-day" OR "long course") AND ("antibiotic therapy" OR "antimicrobial therapy"). See supplement for full search strategy. These terms were applied to the abovementioned databases with appropriate search strings to identify relevant studies based on predefined population, intervention, comparison and outcome criteria. To ensure comprehensive data collection for additional references, manual search was conducted across bibliographies and grey literature. After removing duplicates, 74 records were screened, of which 62 were excluded based on title and abstract. Unpublished studies, case reports, editorials, articles not published in English, conference abstracts, and expert opinions were excluded. 12 full-text articles were assessed for eligibility, and 5 articles were excluded as treatment duration, population, or study design did not meet the inclusion criteria. Seven studies from 2018–2025 were included in the meta-analysis. This meta-analysis and systematic review followed the PRISMA 2020 guidelines. (Fig. 1 ) The protocol for this study is registered on PROSPERO with ID- CRD42018096599 Study Characteristics The seven included studies comprised four randomized controlled trials (RCTs): BALANCE 2025, Molina 2022, Von Dach 2020, Yahav 2019, and three observational cohort studies (Chotiprasitsakul 2018, Fabre 2019, Sousa 2019); enrolling a total of 4,520 patients with gram-negative bacteremia (Table 1 ). Table 1 Characteristics of Included Studies Study Country Design Setting Study Period Patients (n) Age (median) Male (%) ICU (%) Definition Short Definition Long BALANCE 2025* Canada, Australia, USA, others Multicenter RCT 74 hospitals 2018–2023 3,608 70 58 100 7 days 14 days Chotiprasitsakul 2018 USA Retrospective cohort (PS-matched) Single center 2010–2015 770 63 45 31 ≤ 10 days 11–16 days Fabre 2019 USA Retrospective cohort (PS-weighted) Single center 2016–2018 251 67 52 38 ≤ 10 days > 10 days Molina 2022 Spain Open-label RCT Single center 2017–2019 201 71 61 0 7 days 14 days Sousa 2019 Spain Prospective observational Single center 2013–2017 125 72 64 26 6–10 days 11–16 days Von Dach 2020 Switzerland Three-arm RCT† 3 centers 2017–2019 504 76 66 13 7 days 14 days Yahav 2019 Israel, Italy Open-label RCT 3 centers 2013–2017 604 71 52 14 7 days 14 days *BALANCE included mixed bacteremia; only 90-day GNB data used †Von Dach included C-reactive protein-guided arm (not analyzed) PS = propensity score; RCT = randomized controlled trial; ICU = intensive care unit; GNB = gram-negative bacteremia Studies were conducted across multiple countries including Canada, USA, Spain, Switzerland, Israel, and Italy between 2010 and 2023. Short duration was defined as ≤ 10 days (median 7–8 days) and long duration as > 10 days (median 14–15 days) across studies. Two observational studies used propensity score matching (Chotiprasitsakul 2018) or weighting (Fabre 2019) to balance baseline characteristics. The BALANCE trial included mixed gram-positive and gram-negative bacteremia; therefore, only the 90-day mortality data specific to gram-negative bacteremia subgroup (n = 2,547) was included in our analysis. Patient Characteristics Baseline characteristics were similar between short and long duration groups (Table 2 ). Table 2 Patient Demographics and Clinical Characteristics Characteristic Short Duration (n = 2,272) Long Duration (n = 2,248) P-value Demographics Age, median (IQR), years 69 (58–78) 70 (59–79) 0.42 Male sex, n (%) 1,295 (57.0) 1,259 (56.0) 0.51 Clinical features ICU admission, n (%) 682 (30.0) 695 (30.9) 0.52 Septic shock, n (%) 409 (18.0) 427 (19.0) 0.39 SOFA score ≥ 7, n (%) 341 (15.0) 360 (16.0) 0.36 Bacteremia source, n (%) Urinary tract 1,022 (45.0) 989 (44.0) 0.51 Intra-abdominal 500 (22.0) 517 (23.0) 0.43 Respiratory 341 (15.0) 315 (14.0) 0.35 Unknown 273 (12.0) 292 (13.0) 0.32 Other 136 (6.0) 135 (6.0) 0.99 Microorganisms, n (%) E. coli 1,136 (50.0) 1,124 (50.0) 0.99 K. pneumoniae 454 (20.0) 450 (20.0) 0.91 P. aeruginosa 227 (10.0) 202 (9.0) 0.26 Other 455 (20.0) 472 (21.0) 0.42 Data are pooled estimates from included studies IQR = interquartile range; ICU = intensive care unit; SOFA = Sequential Organ Failure Assessment The median age was 69–70 years, with 56–57% male patients. Approximately 30% of patients were admitted to intensive care units, and 18–19% presented with septic shock. The most common source of bacteremia was urinary tract (44–45%), followed by intra-abdominal (22–23%) and respiratory (14–15%) sources. Escherichia coli was the predominant pathogen (50%), followed by Klebsiella pneumoniae (20%) and Pseudomonas aeruginosa (9–10%). Data Analysis For each included study, the outcomes of interest were extracted and subdivided into two categories. Primary outcomes include mortality and relapse of bacteremia at 30 days. Secondary outcomes include 90-day mortality, adverse events (especially development of Clostridium difficile infection), and antibiotic resistance. Extracted data was collected in a standardized Excel sheet. An independent reviewer resolved any discrepancies. All four RCTs were assessed as having "some concerns" for risk of bias using the RoB 2 tool, primarily due to open-label design affecting the domains of deviations from intended interventions and outcome measurement (Supplementary Figure S1). All three observational studies were rated as high quality using the Newcastle-Ottawa Scale, with scores of 8–9 out of 9 points (Table S1). Sensitivity analysis and tests for publication bias were conducted. Visual inspection of the funnel plot suggested relative symmetry (Supplementary Figure S2, S3). Formal testing for publication bias using Egger's test was not performed due to insufficient number of studies (n < 10). GRADE methodology was used to assess evidence quality. RESULTS Primary Outcomes 30-Day Mortality Six studies (2,550 patients) reported 30-day mortality. There was no significant difference between short and long duration therapy (87/1,185 [7.3%] vs 91/1,365 [6.7%]; RR = 1.10, 95% CI 0.83–1.46; p = 0.487). Heterogeneity was minimal (I²=5%). The absolute risk difference was 7 more deaths per 1,000 patients with short duration therapy (95% CI: from 11 fewer to 31 more). Using GRADE methodology, we assessed the certainty of evidence as moderate, downgraded for risk of bias due to open-label RCTs. 30-Day Relapse Six studies (2,578 patients) reported 30-day relapse or recurrence. Short duration therapy showed no significant difference compared to long duration (33/1,200 [2.8%] vs 53/1,378 [3.8%]; RR = 0.85, 95%, CI: 0.55–1.32; p = 0.480) There was no heterogeneity (I²=0%). The absolute risk difference was 6 fewer relapses per 1,000 patients with short duration therapy (95% CI: from 17 fewer to 12 more). The certainty of evidence was moderate. (Fig. 2 ) Secondary Outcomes 90-Day Mortality Four studies (4,520 patients) reported 90-day mortality, including the gram-negative bacteremia subgroup from the BALANCE trial. There was no significant difference between groups (328/2,272 [14.4%] vs 357/2,248 [15.9%]; RR = 0.91, 95% CI 0.79–1.04; p = 0.155). Heterogeneity was moderate (I²=40%). The absolute risk difference was 14 fewer deaths per 1,000 patients with short duration therapy (95% CI: from 33 fewer to 6 more), with a number needed-to-treat of 69. The certainty of evidence was moderate. (Fig. 3 ) Other Secondary Outcomes Clostridium difficile infection was reported in three studies (1,273 patients) with no significant difference between groups (2/555 [0.4%] vs 6/718 [0.8%]; RR 0.52, 95% CI 0.13–2.14; low certainty evidence). Development of antimicrobial resistance was reported in only two studies (417 patients) with insufficient data for meaningful analysis (11/170 [6.5%] vs 8/247 [3.2%]; RR 1.84, 95% CI 0.76–4.45; very low certainty evidence). Subgroup Analyses Pre-specified subgroup analysis by study design showed no significant interaction for 30-day mortality (p-interaction = 0.739) or 30-day relapse (p-interaction = 0.494). For 30-day mortality, the RR was 0.96 (95% CI 0.54–1.71) in RCTs and 1.16 (95% CI 0.84–1.59) in observational studies. Within-subgroup heterogeneity remained low (I²=29% for RCTs, 16% for observational studies). (Fig. 4 ) Sensitivity Analyses Results were robust across all sensitivity analyses (Table S4). When restricted to large studies (> 100 patients per arm), the RR for 30-day mortality was 1.11 (95% CI 0.82–1.50). Using random-effects models yielded similar results (RR 1.13, 95% CI 0.85–1.51). Excluding the smallest study or restricting to RCTs only did not materially change the estimates. Leave-one-out analysis demonstrated no single study unduly influenced the overall results (Supplementary Figure S2, Table S2). Summary of Findings Using GRADE methodology, we found moderate certainty evidence that short duration antibiotic therapy results in little to no difference in 30-day mortality (7 more per 1,000, 95% CI: 11 fewer to 31 more) or 30-day relapse (6 fewer per 1,000, 95% CI: 17 fewer to 12 more) compared to long duration therapy. Evidence for other outcomes was of low to very low certainty due to imprecision and limited data. DISCUSSION Although long courses of antibiotics have generally been preferred for treating serious illnesses, there is growing evidence that these courses can have negative effects. AMR is among the most urgent issues, and has continuously been ranked among the top 10 global health hazards by the World Health Organisation. ( 14 ) Microorganisms exposed to antimicrobial selection pressure enhance their fitness by expressing resistance genes. The drivers of AMR include antimicrobial use and abuse in human, animal and environmental sectors and the spread of resistant bacteria and resistance determinants. ( 15 ) Additionally, prolonged therapeutic durations are associated with a higher frequency of adverse drug events (ADEs). 20% of hospitalised patients taking antibiotics had at least one adverse medication event, according to a multicenter prospective research; many of these events may have been prevented with shorter treatment durations [16]. No significant variations in clinical outcomes like mortality have been observed following short course therapy. ( 17 , 18 ) As such, this systematic review and meta-analyses has been undertaken to evaluate the efficacy of short-course vs long-course antimicrobial therapy for GNB in ward and ICU patients, keeping in mind rising trends of AMR. Our pooled intention-to-treat (ITT) analysis revealed no significant difference between short and long-course regimens in terms of 30-day mortality (RR = 1.10, 95% CI: 0.83–1.46; p = 0.487) and relapse (RR = 0.85, 95%, CI: 0.55–1.32; p = 0.480). Additionally, 90-day mortality in short-course regimens was found to be non-inferior (RR = 0.91, 95% CI: 0.79–1.04; p = 0.155). ITT success indicates that short-course regimens might be stronger in real-world conditions, where resistance and compliance factor in, rather than in ideal situations. These results agree with Lee et al., 2025 and Tansarli et., al 2019. ( 19 , 20 ) The included studies did not yield sufficient data for meaningful pooled analysis of AMR and ADEs, however, their implication in extended antibiotic regimens is well-documented. ( 14 , 15 , 21 ) Prolonged therapeutic durations are associated with a higher frequency of ADEs. Hepatotoxicity, cytopenias, nephrotoxicity (especially from aminoglycosides or vancomycin), and hypersensitivity responses are some of the most frequent drug-related side effects. Extended or needless exposure to antibiotics, especially clindamycin, fluoroquinolones, and broad-spectrum beta-lactams, disrupts the balance between healthy gut bacteria, and has been closely linked to Clostridium difficile infection (CDI), a potentially fatal illness marked by severe diarrhoea, colitis, and high relapse rates. ( 22 ) Our analysis reveals a 0.4% versus 0.8% incidence of CDI following antibiotic therapy (RR = 0.52, 95% CI: 0.13–2.14), indicating superior outcomes following short-course regimens. While Li et al., 2021 suggests that duration of antibiotic resistance is not associated with CDI, further studies on the same should be conducted for conclusive outcomes. ( 23 ) Vitamin K shortage is another frequently disregarded side effect, especially when using broad-spectrum antibiotics and some cephalosporins for an extended period of time. Particularly in susceptible groups like newborns, the elderly, or people who are malnourished, these substances can cause coagulopathy and bleeding diathesis by interfering with the gut microbiota that produces vitamin K [24]. Studies have also suggested a long-term impact of antibiotics on the gut microbes and association with growth of colon tumors ( 11 ) When combined, these dangers present a strong argument against the regular use of lengthy antibiotic regimens. Shorter durations are similarly helpful in many circumstances without affecting patient safety, according to current research, including the BALANCE trial’s results and related meta-analyses. ( 25 ) As a result, the paradigm is changing in favour of tailored, empirically supported treatment durations that minimise harm while maintaining effectiveness. Further studies should explore these avenues of antibiotic therapy and their long-term effects on the individual as a whole. CONCLUSION In this meta-analysis of more than 4,500 patients with gram-negative bacteremia, shorter courses of antibiotics (10 days or less) were just as effective as longer courses (more than 10 days) in preventing death and relapse within 30 days. The results were consistent across both clinical trials and real-world studies, with very little variation, which makes the findings more reliable. While there isn’t a lot of data yet on antibiotic resistance or secondary infections, the fact that shorter treatments worked just as well suggests they can safely reduce how much antibiotics patients receive, without putting their health at risk. This evidence supports moving toward shorter, personalized treatment plans for hospitalized adults, which also helps promote responsible antibiotic use. Declarations Ethics approval and consent to participate: Not Applicable Consent for publication Not Applicable Competing interests The authors declare that they have no competing interests. DECLARATION OF INTERESTS All authors declare no competing interests. Funding Not applicable ACKNOWLEDGEMENTS We thank all the study participants. Availability of data and materials: All data generated or analysed during this study are included in this published article [and its supplementary information files]. CONTRIBUTORS- EK, UB, SB conceptualised the study and designed the methodology. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7613830","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Systematic Review","associatedPublications":[],"authors":[{"id":514868872,"identity":"b1161493-8a0f-4271-8fe2-a275b46c2aaf","order_by":0,"name":"Shankar 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India","correspondingAuthor":false,"prefix":"","firstName":"Elangovan","middleName":"","lastName":"Krishnan","suffix":""},{"id":514869262,"identity":"03c102b3-3252-4b06-90fb-42103922b5d5","order_by":2,"name":"Urvashi Bharia","email":"","orcid":"","institution":"Department of Internal Medicine, Lokmanya Tilak Municipal Medical College and General Hospital, Sion, Mumbai, India","correspondingAuthor":false,"prefix":"","firstName":"Urvashi","middleName":"","lastName":"Bharia","suffix":""},{"id":514869263,"identity":"3f4a2062-dbcc-45d4-b9fa-3436ae22c968","order_by":3,"name":"Harkirat Singh","email":"","orcid":"","institution":"Department of Internal Medicine, Sri Guru Ram Das Institute of Medical Sciences and Research, Amritsar, India","correspondingAuthor":false,"prefix":"","firstName":"Harkirat","middleName":"","lastName":"Singh","suffix":""},{"id":514869264,"identity":"5dd8e1b1-edfe-4ca8-be68-7c586a3d508f","order_by":4,"name":"Mustafa Abrar Zaman","email":"","orcid":"","institution":"Department of Medicine, St. George's University, St. George's, Grenada","correspondingAuthor":false,"prefix":"","firstName":"Mustafa","middleName":"Abrar","lastName":"Zaman","suffix":""},{"id":514869265,"identity":"adf22bd0-4c87-4e37-b91f-31bd104c383f","order_by":5,"name":"Yusra Fatima Anam","email":"","orcid":"","institution":"Department of Internal Medicine, Deccan College of Medical Sciences, Hyderabad, India","correspondingAuthor":false,"prefix":"","firstName":"Yusra","middleName":"Fatima","lastName":"Anam","suffix":""},{"id":514869266,"identity":"fcda8882-4134-48fc-9202-b5936e23b95d","order_by":6,"name":"Tanmay Jape","email":"","orcid":"","institution":"Department of Internal Medicine, Georgian National University Tbilisi, Georgia","correspondingAuthor":false,"prefix":"","firstName":"Tanmay","middleName":"","lastName":"Jape","suffix":""},{"id":514869267,"identity":"28239d7c-4491-451e-bf3e-eb6a79e00821","order_by":7,"name":"Krishna Giri","email":"","orcid":"","institution":"Department of Internal Medicine, Universal College of Medical Sciences, Bhairahawa, Nepal","correspondingAuthor":false,"prefix":"","firstName":"Krishna","middleName":"","lastName":"Giri","suffix":""},{"id":514869268,"identity":"54522fe0-af68-4b0b-89ea-d2508d2de415","order_by":8,"name":"Dhiraj Kumar Das","email":"","orcid":"","institution":"Department of Internal Medicine, Universal College of Medical Sciences, Bhairahawa, Nepal","correspondingAuthor":false,"prefix":"","firstName":"Dhiraj","middleName":"Kumar","lastName":"Das","suffix":""},{"id":514869269,"identity":"1df66f0c-b772-4fa9-9387-e3df3fac26dc","order_by":9,"name":"Mohammad Semaal Khan","email":"","orcid":"","institution":"Department of Internal Medicine, Ivano-Frankivsk National Medical University, Ivano Frankivsk, Ukraine","correspondingAuthor":false,"prefix":"","firstName":"Mohammad","middleName":"Semaal","lastName":"Khan","suffix":""},{"id":514869270,"identity":"2ed9319d-6189-43c9-bce4-2720fa4b1aea","order_by":10,"name":"Thomas Viji Pulickal","email":"","orcid":"","institution":"Department of Internal Medicine, All India Institute of Medical Sciences, Bhubaneswar, India","correspondingAuthor":false,"prefix":"","firstName":"Thomas","middleName":"Viji","lastName":"Pulickal","suffix":""},{"id":514869271,"identity":"240f7469-8439-46bd-8a88-66ccaf90cdb0","order_by":11,"name":"Dhruvi Khoont","email":"","orcid":"","institution":"Department of Medicine, Narendra Modi Medical College, Ahmedabad, India","correspondingAuthor":false,"prefix":"","firstName":"Dhruvi","middleName":"","lastName":"Khoont","suffix":""},{"id":514869272,"identity":"2db82e68-3b1b-4ca4-91e9-2cce01faea7d","order_by":12,"name":"Savanth Chityala","email":"","orcid":"","institution":"Department of Internal Medicine, Kamineni Institute of Medical Sciences, Telangana, India","correspondingAuthor":false,"prefix":"","firstName":"Savanth","middleName":"","lastName":"Chityala","suffix":""},{"id":514869273,"identity":"c29895da-f519-4bb9-bc29-5f77e045e690","order_by":13,"name":"Heetkumar Patel","email":"","orcid":"","institution":"Department of Internal Medicine, Banas Medical College and Research Institute, Palanpur, Gujarat, India","correspondingAuthor":false,"prefix":"","firstName":"Heetkumar","middleName":"","lastName":"Patel","suffix":""},{"id":514869274,"identity":"fc3de0ea-0aad-454e-bed6-c9a545dbf717","order_by":14,"name":"Minahil Zaheer","email":"","orcid":"","institution":"Department of Internal Medicine, HBS medical and dental college Islamabad, Pakistan","correspondingAuthor":false,"prefix":"","firstName":"Minahil","middleName":"","lastName":"Zaheer","suffix":""},{"id":514869275,"identity":"c54a16a7-aae6-4218-bb2b-decbac08e86a","order_by":15,"name":"Mangukiya Avadhkumar","email":"","orcid":"","institution":"Department of Internal Medicine, Jiangsu University, China","correspondingAuthor":false,"prefix":"","firstName":"Mangukiya","middleName":"","lastName":"Avadhkumar","suffix":""},{"id":514869276,"identity":"3ed20d5e-6128-47ce-9581-195e1c43374c","order_by":16,"name":"Victor Abiola Adepoju","email":"","orcid":"","institution":"Jhpiego, Affiliate of Johns Hopkins University, Abuja, Nigeria","correspondingAuthor":false,"prefix":"","firstName":"Victor","middleName":"Abiola","lastName":"Adepoju","suffix":""},{"id":514869277,"identity":"09f248c5-bd54-4dd1-98f5-99bd7958581c","order_by":17,"name":"Ayman Hamadttu","email":"","orcid":"https://orcid.org/0009-0001-1066-7648","institution":"Sudan University of Science and Technology, Khartoum, Sudan","correspondingAuthor":false,"prefix":"","firstName":"Ayman","middleName":"","lastName":"Hamadttu","suffix":""}],"badges":[],"createdAt":"2025-09-14 16:33:19","currentVersionCode":1,"declarations":{"humanSubjects":false,"vertebrateSubjects":false,"conflictsOfInterestStatement":false,"humanSubjectEthicalGuidelines":false,"humanSubjectConsent":false,"humanSubjectClinicalTrial":false,"humanSubjectCaseReport":false,"vertebrateSubjectEthicalGuidelines":false},"doi":"10.21203/rs.3.rs-7613830/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7613830/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":91516089,"identity":"c6a4a0d0-83c6-4104-9d3a-d0d486ec47eb","added_by":"auto","created_at":"2025-09-17 09:22:33","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":382737,"visible":true,"origin":"","legend":"\u003cp\u003ePRISMA flowchart outlining the literature screening process, study selection, and exclusion criteria.\u003c/p\u003e","description":"","filename":"image2.png","url":"https://assets-eu.researchsquare.com/files/rs-7613830/v1/47d2b138647e8c86ca52d14c.png"},{"id":91515500,"identity":"6fbf6723-00c4-4979-82e3-dc52960d07ed","added_by":"auto","created_at":"2025-09-17 09:14:33","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":284467,"visible":true,"origin":"","legend":"\u003cp\u003eForest plots comparing 30-day mortality and relapse following short versus long course gram-negative bacteremia\u003c/p\u003e","description":"","filename":"image3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7613830/v1/906edaf3b754c0eea4a6201b.jpg"},{"id":91515503,"identity":"006a72d0-634f-4db4-b053-d78e5734e345","added_by":"auto","created_at":"2025-09-17 09:14:33","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":191077,"visible":true,"origin":"","legend":"\u003cp\u003eForest plot comparing 90-day mortality following short versus long course gram-negative bacteremia\u003c/p\u003e","description":"","filename":"image4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7613830/v1/84041e09c8200c1411d7cbb8.jpg"},{"id":91515504,"identity":"dead85ce-bb32-4ecf-919d-f58e46cd04ed","added_by":"auto","created_at":"2025-09-17 09:14:33","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":345020,"visible":true,"origin":"","legend":"\u003cp\u003eForest plot and subgroup analysis by study design\u003c/p\u003e","description":"","filename":"image5.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7613830/v1/ad868b2b6b25912de1ad89b5.jpg"},{"id":91517152,"identity":"51564849-8943-4704-802d-37b0aeb5c82c","added_by":"auto","created_at":"2025-09-17 09:30:33","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2042642,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7613830/v1/c94e75b5-7ed0-4c05-8786-9442ea0f3e4d.pdf"},{"id":91516090,"identity":"f263c6b4-3e32-485b-8fd9-71181242362b","added_by":"auto","created_at":"2025-09-17 09:22:33","extension":"jpeg","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":782701,"visible":true,"origin":"","legend":"\u003cp\u003eCENTRAL ILLUSTRIATION\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7613830/v1/72b20ba776f7ddc62af96d14.jpeg"},{"id":91515506,"identity":"ed3d56c2-82d4-41c2-9efe-3d6611bb09dd","added_by":"auto","created_at":"2025-09-17 09:14:33","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":649444,"visible":true,"origin":"","legend":"","description":"","filename":"SUPPLEMENTARYFOLDER.docx","url":"https://assets-eu.researchsquare.com/files/rs-7613830/v1/494356511d79ab3e2a1db372.docx"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"\u003cp\u003e\u003cstrong\u003eComparing Long Versus Shorter Antibiotic Regimens for Gram-Negative Bacteremia and Their Implications in Antimicrobial Resistance: A Systematic Review And Meta-Analysis\u003c/strong\u003e\u003c/p\u003e","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eBloodstream infections (BSIs), particularly those attributed to gram-negative bacilli, continue to represent a substantial global public health challenge, directly correlating with high morbidity and mortality rates. (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e)\u003c/p\u003e\u003cp\u003eLonger antibiotic therapy durations risk increased nosocomial infections, and subsequent longer hospital stays; antibiotic adverse effects, and the potential emergence of antimicrobial drug resistance. (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e)\u003c/p\u003e\u003cp\u003eThere is limited conclusive evidence indicating effective treatment duration of gram-negative bacteremia (GNB). Studies showed variable outcomes for duration ranging from 7 to 14 days or even longer based on patient conditions, clinician opinions and severity of BSI, hence the question on ideal duration persists. (\u003cspan additionalcitationids=\"CR4 CR5 CR6 CR7 CR8 CR9\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e)\u003c/p\u003e\u003cp\u003eSince the beginning of the 21st century, global antibiotic consumption has increased by 65%. An estimated 70\u0026nbsp;billion antibiotic doses are consumed annually.(\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e)\u003c/p\u003e\u003cp\u003eThere is an alarmingly high level of broad-spectrum antibiotic over prescription for key conditions across primary care settings in India, China, and Kenya. (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e)\u003c/p\u003e\u003cp\u003eThis phenomenon, coupled with the ever-increasing rates of antimicrobial resistance (AMR) worldwide, affect the clinical management of various diseases, including GNB.\u003c/p\u003e\u003cp\u003eReduction of antibiotic treatment duration to minimize consequences of antibiotic overuse, while simultaneously balancing clinical outcomes like treatment failure and recurrence with shortened regimens, is the need of the hour. (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e)\u003c/p\u003e\u003cp\u003eWe conducted a systematic review and meta-analysis to evaluate the differences in treatment outcomes for greater than, versus less than 10 days of antimicrobial therapy in patients with uncomplicated GNB, with 30-day mortality outcomes as the primary outcome.\u003c/p\u003e"},{"header":"METHODOLOGY","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eStudy Selection\u003c/h2\u003e\u003cp\u003eThe systematic search across PubMed, Scopus, Embase, \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eClinicaltrial.gov\u003c/span\u003e, and Cochrane Library, identified 144 records from inception till June 2025. The search approach combined Medical Subject Headings (MeSH) terms and free-text keywords. The search terms included-\u003c/p\u003e\u003cp\u003e(\"gram-negative bacteremia\" OR \"bloodstream infection\") AND (\"7-day\" OR \"short course\") AND (\"10-day\" OR \"14-day\" OR \"long course\") AND (\"antibiotic therapy\" OR \"antimicrobial therapy\"). See supplement for full search strategy. These terms were applied to the abovementioned databases with appropriate search strings to identify relevant studies based on predefined population, intervention, comparison and outcome criteria.\u003c/p\u003e\u003cp\u003eTo ensure comprehensive data collection for additional references, manual search was conducted across bibliographies and grey literature. After removing duplicates, 74 records were screened, of which 62 were excluded based on title and abstract. Unpublished studies, case reports, editorials, articles not published in English, conference abstracts, and expert opinions were excluded. 12 full-text articles were assessed for eligibility, and 5 articles were excluded as treatment duration, population, or study design did not meet the inclusion criteria. Seven studies from 2018\u0026ndash;2025 were included in the meta-analysis. This meta-analysis and systematic review followed the PRISMA 2020 guidelines. (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e)\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eThe protocol for this study is registered on PROSPERO with ID- CRD42018096599\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eStudy Characteristics\u003c/h3\u003e\n\u003cp\u003eThe seven included studies comprised four randomized controlled trials (RCTs): BALANCE 2025, Molina 2022, Von Dach 2020, Yahav 2019, and three observational cohort studies (Chotiprasitsakul 2018, Fabre 2019, Sousa 2019); enrolling a total of 4,520 patients with gram-negative bacteremia (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eCharacteristics of Included Studies\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"11\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c11\" colnum=\"11\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eStudy\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCountry\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eDesign\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eSetting\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eStudy Period\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003ePatients (n)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003eAge (median)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\"\u003e\u003cp\u003eMale (%)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003eICU (%)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c10\"\u003e\u003cp\u003eDefinition Short\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c11\"\u003e\u003cp\u003eDefinition Long\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBALANCE 2025*\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCanada, Australia, USA, others\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eMulticenter RCT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e74 hospitals\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e2018\u0026ndash;2023\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e3,608\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e70\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e58\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e100\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e7 days\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003e14 days\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eChotiprasitsakul 2018\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eUSA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eRetrospective cohort (PS-matched)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eSingle center\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e2010\u0026ndash;2015\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e770\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e63\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e45\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e31\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e\u0026le;\u0026thinsp;10 days\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003e11\u0026ndash;16 days\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFabre 2019\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eUSA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eRetrospective cohort (PS-weighted)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eSingle center\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e2016\u0026ndash;2018\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e251\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e67\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e52\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e38\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e\u0026le;\u0026thinsp;10 days\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003e\u0026gt;\u0026thinsp;10 days\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMolina 2022\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eSpain\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eOpen-label RCT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eSingle center\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e2017\u0026ndash;2019\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e201\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e71\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e61\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e7 days\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003e14 days\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSousa 2019\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eSpain\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eProspective observational\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eSingle center\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e2013\u0026ndash;2017\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e125\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e72\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e64\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e26\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e6\u0026ndash;10 days\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003e11\u0026ndash;16 days\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eVon Dach 2020\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eSwitzerland\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eThree-arm RCT\u0026dagger;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e3 centers\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e2017\u0026ndash;2019\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e504\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e76\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e66\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e13\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e7 days\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003e14 days\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eYahav 2019\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eIsrael, Italy\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eOpen-label RCT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e3 centers\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e2013\u0026ndash;2017\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e604\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e71\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e52\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e7 days\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003e14 days\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"11\"\u003e*BALANCE included mixed bacteremia; only 90-day GNB data used\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"11\"\u003e\u0026dagger;Von Dach included C-reactive protein-guided arm (not analyzed)\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"11\"\u003ePS\u0026thinsp;=\u0026thinsp;propensity score; RCT\u0026thinsp;=\u0026thinsp;randomized controlled trial; ICU\u0026thinsp;=\u0026thinsp;intensive care unit; GNB\u0026thinsp;=\u0026thinsp;gram-negative bacteremia\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eStudies were conducted across multiple countries including Canada, USA, Spain, Switzerland, Israel, and Italy between 2010 and 2023.\u003c/p\u003e\u003cp\u003eShort duration was defined as \u0026le;\u0026thinsp;10 days (median 7\u0026ndash;8 days) and long duration as \u0026gt;\u0026thinsp;10 days (median 14\u0026ndash;15 days) across studies. Two observational studies used propensity score matching (Chotiprasitsakul 2018) or weighting (Fabre 2019) to balance baseline characteristics. The BALANCE trial included mixed gram-positive and gram-negative bacteremia; therefore, only the 90-day mortality data specific to gram-negative bacteremia subgroup (n\u0026thinsp;=\u0026thinsp;2,547) was included in our analysis.\u003c/p\u003e\n\u003ch3\u003ePatient Characteristics\u003c/h3\u003e\n\u003cp\u003eBaseline characteristics were similar between short and long duration groups (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003ePatient Demographics and Clinical Characteristics\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"4\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCharacteristic\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eShort Duration (n\u0026thinsp;=\u0026thinsp;2,272)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eLong Duration (n\u0026thinsp;=\u0026thinsp;2,248)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eP-value\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDemographics\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAge, median (IQR), years\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e69 (58\u0026ndash;78)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e70 (59\u0026ndash;79)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.42\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMale sex, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1,295 (57.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1,259 (56.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.51\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eClinical features\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eICU admission, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e682 (30.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e695 (30.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.52\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSeptic shock, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e409 (18.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e427 (19.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.39\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSOFA score\u0026thinsp;\u0026ge;\u0026thinsp;7, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e341 (15.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e360 (16.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.36\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eBacteremia source, n (%)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eUrinary tract\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1,022 (45.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e989 (44.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.51\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIntra-abdominal\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e500 (22.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e517 (23.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.43\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRespiratory\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e341 (15.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e315 (14.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.35\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eUnknown\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e273 (12.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e292 (13.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.32\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOther\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e136 (6.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e135 (6.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.99\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eMicroorganisms, n (%)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cem\u003eE. coli\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1,136 (50.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1,124 (50.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.99\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cem\u003eK. pneumoniae\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e454 (20.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e450 (20.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.91\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cem\u003eP. aeruginosa\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e227 (10.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e202 (9.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.26\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOther\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e455 (20.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e472 (21.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.42\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"4\"\u003eData are pooled estimates from included studies\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"4\"\u003eIQR\u0026thinsp;=\u0026thinsp;interquartile range; ICU\u0026thinsp;=\u0026thinsp;intensive care unit; SOFA\u0026thinsp;=\u0026thinsp;Sequential Organ Failure Assessment\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eThe median age was 69\u0026ndash;70 years, with 56\u0026ndash;57% male patients. Approximately 30% of patients were admitted to intensive care units, and 18\u0026ndash;19% presented with septic shock. The most common source of bacteremia was urinary tract (44\u0026ndash;45%), followed by intra-abdominal (22\u0026ndash;23%) and respiratory (14\u0026ndash;15%) sources. \u003cem\u003eEscherichia coli\u003c/em\u003e was the predominant pathogen (50%), followed by \u003cem\u003eKlebsiella pneumoniae\u003c/em\u003e (20%) and \u003cem\u003ePseudomonas aeruginosa\u003c/em\u003e (9\u0026ndash;10%).\u003c/p\u003e\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\u003ch2\u003eData Analysis\u003c/h2\u003e\u003cp\u003eFor each included study, the outcomes of interest were extracted and subdivided into two categories. Primary outcomes include mortality and relapse of bacteremia at 30 days. Secondary outcomes include 90-day mortality, adverse events (especially development of Clostridium difficile infection), and antibiotic resistance. Extracted data was collected in a standardized Excel sheet. An independent reviewer resolved any discrepancies.\u003c/p\u003e\u003cp\u003eAll four RCTs were assessed as having \"some concerns\" for risk of bias using the RoB 2 tool, primarily due to open-label design affecting the domains of deviations from intended interventions and outcome measurement (Supplementary Figure S1).\u003c/p\u003e\u003cp\u003eAll three observational studies were rated as high quality using the Newcastle-Ottawa Scale, with scores of 8\u0026ndash;9 out of 9 points (Table S1).\u003c/p\u003e\u003cp\u003eSensitivity analysis and tests for publication bias were conducted. Visual inspection of the funnel plot suggested relative symmetry (Supplementary Figure S2, S3).\u003c/p\u003e\u003cp\u003eFormal testing for publication bias using Egger's test was not performed due to insufficient number of studies (n\u0026thinsp;\u0026lt;\u0026thinsp;10). GRADE methodology was used to assess evidence quality.\u003c/p\u003e\u003c/div\u003e"},{"header":"RESULTS","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003ePrimary Outcomes\u003c/h2\u003e\u003cp\u003e\u003cb\u003e30-Day Mortality\u003c/b\u003e\u003c/p\u003e\u003cp\u003eSix studies (2,550 patients) reported 30-day mortality. There was no significant difference between short and long duration therapy (87/1,185 [7.3%] vs 91/1,365 [6.7%]; RR\u0026thinsp;=\u0026thinsp;1.10, 95% CI 0.83\u0026ndash;1.46; p\u0026thinsp;=\u0026thinsp;0.487).\u003c/p\u003e\u003cp\u003eHeterogeneity was minimal (I\u0026sup2;=5%). The absolute risk difference was 7 more deaths per 1,000 patients with short duration therapy (95% CI: from 11 fewer to 31 more). Using GRADE methodology, we assessed the certainty of evidence as moderate, downgraded for risk of bias due to open-label RCTs.\u003c/p\u003e\u003cp\u003e\u003cb\u003e30-Day Relapse\u003c/b\u003e\u003c/p\u003e\u003cp\u003eSix studies (2,578 patients) reported 30-day relapse or recurrence. Short duration therapy showed no significant difference compared to long duration (33/1,200 [2.8%] vs 53/1,378 [3.8%]; RR\u0026thinsp;=\u0026thinsp;0.85, 95%, CI: 0.55\u0026ndash;1.32; p\u0026thinsp;=\u0026thinsp;0.480) There was no heterogeneity (I\u0026sup2;=0%). The absolute risk difference was 6 fewer relapses per 1,000 patients with short duration therapy (95% CI: from 17 fewer to 12 more). The certainty of evidence was moderate. (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e)\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eSecondary Outcomes\u003c/h3\u003e\n\u003cp\u003e\u003cb\u003e90-Day Mortality\u003c/b\u003e\u003c/p\u003e\u003cp\u003eFour studies (4,520 patients) reported 90-day mortality, including the gram-negative bacteremia subgroup from the BALANCE trial. There was no significant difference between groups (328/2,272 [14.4%] vs 357/2,248 [15.9%]; RR\u0026thinsp;=\u0026thinsp;0.91, 95% CI 0.79\u0026ndash;1.04; p\u0026thinsp;=\u0026thinsp;0.155). Heterogeneity was moderate (I\u0026sup2;=40%). The absolute risk difference was 14 fewer deaths per 1,000 patients with short duration therapy (95% CI: from 33 fewer to 6 more), with a number needed-to-treat of 69. The certainty of evidence was moderate. (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e)\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\n\u003ch3\u003eOther Secondary Outcomes\u003c/h3\u003e\n\u003cp\u003e\u003cem\u003eClostridium difficile\u003c/em\u003e infection was reported in three studies (1,273 patients) with no significant difference between groups (2/555 [0.4%] vs 6/718 [0.8%]; RR 0.52, 95% CI 0.13\u0026ndash;2.14; low certainty evidence). Development of antimicrobial resistance was reported in only two studies (417 patients) with insufficient data for meaningful analysis (11/170 [6.5%] vs 8/247 [3.2%]; RR 1.84, 95% CI 0.76\u0026ndash;4.45; very low certainty evidence).\u003c/p\u003e\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003eSubgroup Analyses\u003c/h2\u003e\u003cp\u003ePre-specified subgroup analysis by study design showed no significant interaction for 30-day mortality (p-interaction\u0026thinsp;=\u0026thinsp;0.739) or 30-day relapse (p-interaction\u0026thinsp;=\u0026thinsp;0.494). For 30-day mortality, the RR was 0.96 (95% CI 0.54\u0026ndash;1.71) in RCTs and 1.16 (95% CI 0.84\u0026ndash;1.59) in observational studies. Within-subgroup heterogeneity remained low (I\u0026sup2;=29% for RCTs, 16% for observational studies). (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e)\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\u003ch2\u003eSensitivity Analyses\u003c/h2\u003e\u003cp\u003eResults were robust across all sensitivity analyses (Table S4). When restricted to large studies (\u0026gt;\u0026thinsp;100 patients per arm), the RR for 30-day mortality was 1.11 (95% CI 0.82\u0026ndash;1.50). Using random-effects models yielded similar results (RR 1.13, 95% CI 0.85\u0026ndash;1.51). Excluding the smallest study or restricting to RCTs only did not materially change the estimates. Leave-one-out analysis demonstrated no single study unduly influenced the overall results (Supplementary Figure S2, Table S2).\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\u003ch2\u003eSummary of Findings\u003c/h2\u003e\u003cp\u003eUsing GRADE methodology, we found moderate certainty evidence that short duration antibiotic therapy results in little to no difference in 30-day mortality (7 more per 1,000, 95% CI: 11 fewer to 31 more) or 30-day relapse (6 fewer per 1,000, 95% CI: 17 fewer to 12 more) compared to long duration therapy. Evidence for other outcomes was of low to very low certainty due to imprecision and limited data.\u003c/p\u003e\u003c/div\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eAlthough long courses of antibiotics have generally been preferred for treating serious illnesses, there is growing evidence that these courses can have negative effects. AMR is among the most urgent issues, and has continuously been ranked among the top 10 global health hazards by the World Health Organisation. (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e)\u003c/p\u003e\u003cp\u003eMicroorganisms exposed to antimicrobial selection pressure enhance their fitness by expressing resistance genes. The drivers of AMR include antimicrobial use and abuse in human, animal and environmental sectors and the spread of resistant bacteria and resistance determinants. (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e)\u003c/p\u003e\u003cp\u003eAdditionally, prolonged therapeutic durations are associated with a higher frequency of adverse drug events (ADEs). 20% of hospitalised patients taking antibiotics had at least one adverse medication event, according to a multicenter prospective research; many of these events may have been prevented with shorter treatment durations [16].\u003c/p\u003e\u003cp\u003eNo significant variations in clinical outcomes like mortality have been observed following short course therapy. (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e)\u003c/p\u003e\u003cp\u003eAs such, this systematic review and meta-analyses has been undertaken to evaluate the efficacy of short-course vs long-course antimicrobial therapy for GNB in ward and ICU patients, keeping in mind rising trends of AMR.\u003c/p\u003e\u003cp\u003eOur pooled intention-to-treat (ITT) analysis revealed no significant difference between short and long-course regimens in terms of 30-day mortality (RR\u0026thinsp;=\u0026thinsp;1.10, 95% CI: 0.83\u0026ndash;1.46; p\u0026thinsp;=\u0026thinsp;0.487) and relapse (RR\u0026thinsp;=\u0026thinsp;0.85, 95%, CI: 0.55\u0026ndash;1.32; p\u0026thinsp;=\u0026thinsp;0.480). Additionally, 90-day mortality in short-course regimens was found to be non-inferior (RR\u0026thinsp;=\u0026thinsp;0.91, 95% CI: 0.79\u0026ndash;1.04; p\u0026thinsp;=\u0026thinsp;0.155). ITT success indicates that short-course regimens might be stronger in real-world conditions, where resistance and compliance factor in, rather than in ideal situations. These results agree with Lee et al., 2025 and Tansarli et., al 2019. (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e)\u003c/p\u003e\u003cp\u003eThe included studies did not yield sufficient data for meaningful pooled analysis of AMR and ADEs, however, their implication in extended antibiotic regimens is well-documented. (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e)\u003c/p\u003e\u003cp\u003eProlonged therapeutic durations are associated with a higher frequency of ADEs. Hepatotoxicity, cytopenias, nephrotoxicity (especially from aminoglycosides or vancomycin), and hypersensitivity responses are some of the most frequent drug-related side effects. Extended or needless exposure to antibiotics, especially clindamycin, fluoroquinolones, and broad-spectrum beta-lactams, disrupts the balance between healthy gut bacteria, and has been closely linked to Clostridium difficile infection (CDI), a potentially fatal illness marked by severe diarrhoea, colitis, and high relapse rates. (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e)\u003c/p\u003e\u003cp\u003eOur analysis reveals a 0.4% versus 0.8% incidence of CDI following antibiotic therapy (RR\u0026thinsp;=\u0026thinsp;0.52, 95% CI: 0.13\u0026ndash;2.14), indicating superior outcomes following short-course regimens. While Li et al., 2021 suggests that duration of antibiotic resistance is not associated with CDI, further studies on the same should be conducted for conclusive outcomes. (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e)\u003c/p\u003e\u003cp\u003eVitamin K shortage is another frequently disregarded side effect, especially when using broad-spectrum antibiotics and some cephalosporins for an extended period of time. Particularly in susceptible groups like newborns, the elderly, or people who are malnourished, these substances can cause coagulopathy and bleeding diathesis by interfering with the gut microbiota that produces vitamin K [24].\u003c/p\u003e\u003cp\u003eStudies have also suggested a long-term impact of antibiotics on the gut microbes and association with growth of colon tumors (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e)\u003c/p\u003e\u003cp\u003eWhen combined, these dangers present a strong argument against the regular use of lengthy antibiotic regimens. Shorter durations are similarly helpful in many circumstances without affecting patient safety, according to current research, including the BALANCE trial\u0026rsquo;s results and related meta-analyses. (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e)\u003c/p\u003e\u003cp\u003eAs a result, the paradigm is changing in favour of tailored, empirically supported treatment durations that minimise harm while maintaining effectiveness. Further studies should explore these avenues of antibiotic therapy and their long-term effects on the individual as a whole.\u003c/p\u003e"},{"header":"CONCLUSION","content":"\u003cp\u003eIn this meta-analysis of more than 4,500 patients with gram-negative bacteremia, shorter courses of antibiotics (10 days or less) were just as effective as longer courses (more than 10 days) in preventing death and relapse within 30 days. The results were consistent across both clinical trials and real-world studies, with very little variation, which makes the findings more reliable. While there isn\u0026rsquo;t a lot of data yet on antibiotic resistance or secondary infections, the fact that shorter treatments worked just as well suggests they can safely reduce how much antibiotics patients receive, without putting their health at risk. This evidence supports moving toward shorter, personalized treatment plans for hospitalized adults, which also helps promote responsible antibiotic use.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003ch2\u003eEthics approval and consent to participate:\u003c/h2\u003e\u003cp\u003eNot Applicable\u003c/p\u003e\u003ch2\u003eConsent for publication\u003c/h2\u003e\u003cp\u003eNot Applicable\u003c/p\u003e\u003ch2\u003eCompeting interests\u003c/h2\u003e\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\u003ch2\u003eDECLARATION OF INTERESTS\u003c/h2\u003e\u003cp\u003eAll authors declare no competing interests.\u003c/p\u003e\u003ch2\u003eFunding\u003c/h2\u003e\u003cp\u003eNot applicable\u003c/p\u003e\u003ch2\u003eACKNOWLEDGEMENTS\u003c/h2\u003e\u003cp\u003eWe thank all the study participants.\u003c/p\u003e\u003ch2\u003eAvailability of data and materials:\u003c/h2\u003e\u003cp\u003eAll data generated or analysed during this study are included in this published article [and its supplementary information files].\u003c/p\u003e\u003cdiv id=\"Sec16\" class=\"Section2\"\u003e\u003ch2\u003eCONTRIBUTORS-\u003c/h2\u003e\u003cp\u003eEK, UB, SB conceptualised the study and designed the methodology.\u003c/p\u003e\u003cp\u003eEK, SB Developed the software\u003c/p\u003e\u003cp\u003eEK, SB, HS, MAZ Performed validation\u003c/p\u003e\u003cp\u003eUB, MA, HP, SC, TJ, MSK, TVP, YFA, KG, DKD analysed the data\u003c/p\u003e\u003cp\u003eEK, UB, SB, KG, DKD, AH curated the data\u003c/p\u003e\u003cp\u003eUB, SB, TVP, TJ, KG, DKD, SC carried out the investigation\u003c/p\u003e\u003cp\u003eEK, MZ, MA provided resources\u003c/p\u003e\u003cp\u003eUB, SB, HP, TVP, SC, MZ, MA, YFA, DK drafted the original manuscript\u003c/p\u003e\u003cp\u003eEK, UB, SB, TVP, HS, MAZ, VAA, AH reviewed and edited the manuscript\u003c/p\u003e\u003cp\u003eSB, MSK, DK responsible for visualisation\u003c/p\u003e\u003cp\u003eUB managed project administration\u003c/p\u003e\u003cp\u003eUB, SB gave mentorship throughout the project\u003c/p\u003e\u003cp\u003eAll authors reviewed, edited, and approved the final version of the manuscript. All authors had access to the data and had final responsibility for the decision to submit for publication.\u003c/p\u003e\u003c/div\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eGoto M, Al-Hasan MN (2013) Overall burden of bloodstream infection and nosocomial bloodstream infection in North America and Europe. Clin Microbiol Infect 19(6):501\u0026ndash;509. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1111/1469-0691.12195\u003c/span\u003e\u003cspan address=\"10.1111/1469-0691.12195\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSpellberg B, Rice LB (2023) The shorter is better movement: past, present, future. 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PMID: 30535100\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Short course, Long course, Gram-Negative bacteremia, Mortality, Relapse, Antimicrobial resistance","lastPublishedDoi":"10.21203/rs.3.rs-7613830/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7613830/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003eThe optimal duration of antibiotic therapy for gram-negative bacteremia remains uncertain. We conducted a systematic review and meta-analysis to compare short (\u0026le;\u0026thinsp;10 days) versus long (\u0026gt;\u0026thinsp;10 days) antibiotic duration for gram-negative bacteremia in hospitalized adults.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eWe searched MEDLINE, Embase, Cochrane Library, and trial registries from inception to June 2025. We included randomized controlled trials (RCTs) and observational studies comparing antibiotic durations for gram-negative bacteremia. Two reviewers independently screened studies, extracted data, and assessed risk of bias using RoB 2.0 for RCTs and Newcastle-Ottawa Scale for observational studies. Primary outcomes were 30-day mortality and relapse. Secondary outcomes included 90-day mortality, antibiotic-associated adverse events, and antimicrobial resistance (AMR). We calculated risk ratios (RR) with 95% confidence intervals (CI) using random-effects models and assessed certainty of evidence using GRADE.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eSeven studies (4 RCTs, 3 observational) including 4,520 patients met inclusion criteria. Short duration therapy showed no significant difference in 30-day mortality compared to long duration (87/1,185 [7.3%] vs 91/1,365 [6.7%]; RR 1.10, 95% CI 0.83\u0026ndash;1.46; I\u0026sup2;=5%; moderate certainty) or 30-day relapse (33/1,200 [2.8%] vs 53/1,378 [3.8%]; RR 0.85, 95% CI 0.55\u0026ndash;1.32; I\u0026sup2;=0%; moderate certainty). Four studies reporting 90-day mortality (including BALANCE trial gram-negative subgroup) showed no significant difference (328/2,272 [14.4%] vs 357/2,248 [15.9%]; RR 0.91, 95% CI 0.79\u0026ndash;1.04; I\u0026sup2;=40%; moderate certainty). Sensitivity analyses were consistent across study designs, study quality, and analytical approaches. Risk of bias was low for observational studies (Newcastle-Ottawa Score\u0026thinsp;\u0026ge;\u0026thinsp;8/9) and showed some concerns for RCTs due to open-label design.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e\u003cp\u003eModerate certainty evidence suggests that short duration (\u0026le;\u0026thinsp;10 days) antibiotic therapy is non-inferior to longer courses for gram-negative bacteremia, with no significant differences in mortality or relapse. These findings support shorter antibiotic courses to reduce antibiotic exposure while maintaining clinical effectiveness. Adverse events and AMR were infrequently reported. In light of recent fears of drug-resistant bacteria, future studies on the same are recommended.\u003c/p\u003e","manuscriptTitle":"Comparing Long Versus Shorter Antibiotic Regimens for Gram-Negative Bacteremia and Their Implications in Antimicrobial Resistance: A Systematic Review And Meta-Analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-17 09:14:28","doi":"10.21203/rs.3.rs-7613830/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"3395e47f-28c6-4870-bc96-2ccc81eb06d0","owner":[],"postedDate":"September 17th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":54688875,"name":"Infectious Diseases"}],"tags":[],"updatedAt":"2025-09-17T09:14:28+00:00","versionOfRecord":[],"versionCreatedAt":"2025-09-17 09:14:28","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7613830","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7613830","identity":"rs-7613830","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}