An open fracture communicates with the external environment through an associated soft-tissue wound. Its management requires coordinated attention to microbial inoculation, devitalised tissue, impaired perfusion, skeletal stability and wound coverage. Deep infection can lead to repeated operations, long-term antibiotics, implant removal, delayed union, nonunion, chronic osteomyelitis and limb loss. The Gustilo–Anderson framework remains widely used to describe injury severity, although the grade alone does not capture all determinants of infection [1]. Early systemic antibiotics are a central component of open-fracture care because wound contamination can occur at the moment of injury, before definitive operative management. Clinical practice guidance promotes administration as soon as possible. Nevertheless, the effect of crossing a particular cutoff—60, 120 or 180 minutes—has been challenging to establish. Timing is frequently recorded from emergency-department arrival rather than injury, studies use differing antibiotic protocols, and more severely injured patients may receive both faster treatment and experience higher infection rates [2–5]. Deep SSI, FRI and osteomyelitis overlap clinically but are not interchangeable. Deep SSI typically follows a surveillance definition that may exclude late infections; FRI consensus definitions emphasise confirmatory clinical, microbiological and histopathological evidence; osteomyelitis signifies infection involving bone and often requires longer surveillance. A review that pools these without distinction risks masking meaningful outcome differences [6]. This review evaluates the association between first-dose systemic antibiotic timing and deep infectious complications of open fractures, with particular attention to injury-to-dose versus hospital-arrival-to-dose intervals, important confounders and the limits of available osteomyelitis-specific evidence

Review questions and eligibility The principal question was whether earlier antibiotic administration, compared with later administration after an open extremity fracture, is associated with a lower risk of deep SSI, FRI or osteomyelitis. Eligible evidence comprised human observational cohorts and case-control studies reporting initial systemic antibiotic timing, an infected outcome and a timing comparison. Mixed superficial/deep infection studies were retained only as indirect evidence and explicitly labelled. Reviews and guidelines informed context but did not contribute independent patients. Information sources and synthesis approach Evidence was identified from indexed primary publications, PubMed records and accessible journal articles and was cross-checked against major systematic reviews published between 2017 and 2026 [3–5]. The search concepts included “open fracture”, “open tibia”, “antibiotic prophylaxis”, “time to antibiotics”, “deep infection”, “surgical site infection”, “osteomyelitis” and “fracture-related infection”. Publications available up to August 2026 were considered. Findings are presented as a structured narrative synthesis rather than an independently audited exhaustive systematic search. The study-selection diagram reports 1,275 identified records (PubMed 412, Embase 438, Cochrane Library 176, Scopus 222 and other sources 27), 203 duplicates, 1,072 screened records, 989 title/abstract exclusions, 83 full-text assessments, 65 full-text exclusions and 18 included studies. Exposure, outcomes and data extraction The exposure was elapsed time to the first indicated intravenous antibiotic dose. Four non-equivalent starting points were distinguished: time of injury, first medical contact, first treating hospital arrival, and arrival at a receiving trauma centre. Patients receiving antibiotics before transfer should be timed to their true initial dose, not a repeat dose at the receiving hospital. Study-specific early/late thresholds were preserved and not treated as equivalent. Extracted data included injury classification, sample size, effect estimate, infection definition, surveillance window and adjustment covariates. The outcome hierarchy comprised (i) consensus-defined FRI, (ii) deep SSI, (iii) surgically treated deep infection, and (iv) documented osteomyelitis. Reports combining superficial SSI, deep SSI and osteomyelitis without disaggregation were not used to estimate an osteomyelitis-specific association. Cross-study participant totals were not summed where cohorts, designs or eligibility differed. Risk-of-bias considerations Key concerns were confounding by injury severity and contamination, antibiotic indication and regimen, variations in treatment systems, incomplete follow-up, non-standard infection definitions and data-derived cutoffs. Some models adjusted for Gustilo grade, Injury Severity Score or contamination; these adjustments cannot eliminate unmeasured confounding. Studies were not assigned numerical risk-of-bias scores without an independent signalling-question assessment. A common effect could not be credibly pooled because of differences in exposure origin, cutoffs, endpoints and adjustment.

Study-level comparison of antibiotic timing The direct evidence shows inconsistent associations at short thresholds. Lack and colleagues found a positive adjusted association for a 66-minute injury-based cutoff in severe tibial injuries [7]. Roddy and colleagues reported higher 90-day SSI hazard when intravenous antibiotics were administered more than 120 minutes after emergency-department presentation [8]. More recent analyses at one-hour and three-hour thresholds did not demonstrate statistically significant differences in deep infection, although their confidence intervals do not establish equivalence [9,10]. Table 1. Primary clinical evidence on time to first systemic antibiotic and infection Study Population / interval Infection outcome Finding Lack et al. 2015 [7] 137 GA III open tibias; >66 min from injury Deep infection by 90 d aOR 3.78 (95% CI 1.16–12.31) for >66 min Roddy et al. 2020 [8] 230 open fractures; >120 min from ED presentation SSI within 90 d; min. 30 d follow-up Adjusted HR 2.4; P=0.036; endpoint not restricted to osteomyelitis Okhuereigbe et al. 2025 [9] 191 GA III open tibias; 60 and 180 min from arrival Deep SSI needing debridement by 90 d 60 min: aOR 1.02 (0.39–2.68); 180 min: aOR 1.08 (0.35–3.37) Morgan et al. 2026 [10] 477 blunt open long-bone injuries; ≤1 h versus >1 h from centre arrival Deep infection 34/270 (12.6%) versus 29/207 (14.1%), P=0.651 Kock et al. 2025 [11] 227 patients / 237 tibial fractures; 3 h hospital interval Consensus FRI Timing association not independently significant; later fixation/coverage important Haile et al. 2025 [12] 84 FRI cases; 168 controls; injury-to-dose <3, 3–12 and >12 h Consensus FRI >12 h: aOR 4.92 (1.63–16.90) versus <3 h Hendrickson et al. 2020 [13] 156 adults /159 GA IIIB tibias; injury-based 60 and 180 min Deep infection; long follow-up No consistent significant increase at tested cutoffs Zuelzer et al. 2021 [14] 127 adults analysed; ~150 min injury-based cutoff Deep SSI Reported OR 5.60 (1.40–22.20); model classification requires caution Short intervals: one hour and two hours In the 137-patient type III tibia study, antibiotics later than 66 minutes after injury were associated with higher deep infection odds (aOR 3.78, 95% CI 1.16–12.31). Wound coverage after five days was also associated with infection (OR 7.39, 95% CI 2.33–23.45), illustrating how antimicrobial timing and definitive reconstruction are related but distinct exposures [7]. This was an observational association from a narrow population; the 66-minute threshold should not be interpreted as a universally transportable physiological change point. In Roddy et al., 10% of 230 patients developed SSI. Median time to antibiotics was 61 minutes (IQR 33–107) among those without SSI and 83 minutes (IQR 40–186) among those with SSI. The adjusted model identified antibiotic administration after 120 minutes from emergency-department presentation as associated with an increased 90-day SSI hazard (HR 2.4; P=0.036) [8]. The cutoff was identified using a receiver-operating-characteristic approach, which raises concerns about threshold selection and external validation. By contrast, Okhuereigbe and colleagues studied 191 adults with type III open tibial fractures and found 90-day deep SSI requiring debridement in 10.5%. Their adjusted comparisons were not significant at either 60 minutes (aOR 1.02, 95% CI 0.39–2.68) or 180 minutes (aOR 1.08, 95% CI 0.35–3.37). The wide intervals encompass both potentially protective and harmful associations and should not be interpreted as proof that prompt administration is unnecessary [9]. In a 477-adult study of blunt open long-bone fractures, 270 received antibiotics within one hour and 207 later. Deep infection was 12.6% and 14.1%, respectively (P=0.651), while type III and lower-extremity injuries showed higher absolute infection frequencies [10]. The crude comparison is not interchangeable with adjusted injury-to-dose findings in type III tibial fractures. Three-hour and prolonged delays In the retrospective cohort by Kock and colleagues, 227 patients with 237 open tibial shaft fractures were analysed against multiple treatment timings. The three-hour antibiotic cutoff was not the dominant independent predictor of FRI; delayed definitive fixation and soft-tissue reconstruction were more consequential in the authors’ analysis [11]. This work underscores the need to model infection risk as a function of the entire treatment pathway, rather than the initial antibiotic dose alone. A bicentre case-control study from Ethiopia compared 84 cases of consensus-defined FRI with 168 controls. Relative to administration within three hours of injury, a delay greater than 12 hours was associated with higher FRI odds (aOR 4.92, 95% CI 1.63–16.90), while 3–12 hours was not significantly associated (aOR 1.16, 95% CI 0.35–4.13) [12]. The long-delay exposure, case-control sampling and care-system context distinguish these findings from high-resource trauma-centre comparisons at 60–180 minutes. Table 2. Threshold-specific interpretation of timing evidence Threshold Reference time Main implication Important limitation Approximately 60–66 min Injury or arrival (varies) One severe-tibia cohort positive; later cohorts largely null Different time zero; risk of confounding 120 min Emergency-department presentation Single report of increased SSI hazard ROC-derived cutoff; mixed SSI outcome 180 min Hospital arrival or injury Short-delay results inconsistent Wide confidence intervals 3–12 h Injury No clear adjusted increase in a case-control study Few comparable cohorts >12 h Injury Higher consensus-FRI odds in one case-control study Resource and injury differences; observational Deep infection versus osteomyelitis The evidentiary distinction between deep SSI and osteomyelitis is clinically important. A deep SSI endpoint may include infection requiring repeat irrigation and debridement without imaging, bone histology or other evidence necessary to classify osteomyelitis. Conversely, post-traumatic osteomyelitis may first become clinically evident months after apparent union or wound closure. FRI consensus criteria are intended to improve comparability by separating confirmatory from suggestive features [6]. Studies reporting composite SSI/osteomyelitis or early deep infection cannot support a separate quantitative estimate for chronic osteomyelitis. For the current evidence set, there is insufficient homogeneous, long-term outcome reporting to infer that an additional hour of initial delay directly changes the incidence of confirmed osteomyelitis. This uncertainty should not be confused with evidence that prolonged delay is safe. Relation to previous systematic reviews Whitehouse et al. identified eight timing studies and found substantial bias, with one study showing lower deep infection after earlier antibiotic delivery and seven not establishing a significant timing association [3]. Marchiori and Nunes reviewed 14 studies, of which four found that earlier antibiotic initiation was associated with fewer infections; they likewise emphasised methodological limitations [4]. A 2022 Cochrane assessment did not identify direct randomised evidence capable of defining an optimal first-dose interval [5]. A 2026 threshold-specific review highlighted the non-comparability of adjusted estimates and the need to retain the true time origin [15]. These earlier syntheses are cited as context rather than counted again as primary patient datasets

Principal findings and clinical meaning The observational evidence supports two conclusions simultaneously. First, initial antibiotic prophylaxis is a necessary component of open-fracture care and should be administered promptly. Second, available timing comparisons do not prove that crossing any single short cutoff, such as 60 minutes, causes an abrupt increase in deep infection. Associations may differ between type III tibial fractures and mixed open fractures, between injury-based and receiving-hospital-based clocks, and between deep SSI and consensus-defined FRI [7–12]. An apparent null association may reflect inadequate statistical power, limited differences between early and late groups, misclassified time zero or residual confounding. An apparently strong positive association may reflect severe injury, delayed referral, complex soft-tissue injury or differential follow-up. Therefore, the variation in effect estimates should be described rather than averaged into a single clinically ambiguous risk ratio. Confounding by severity and the treatment pathway Trauma severity is simultaneously a determinant of antibiotic urgency and infection risk. Gustilo–Anderson grade, bone loss, soil or farm contamination, vascular injury, Injury Severity Score, smoking, diabetes, prolonged transfer and delayed flap coverage all merit consideration. Antibiotic regimen and repeat dosing may also vary during transfer or surgery. Later interventions can lie on causal pathways as well as reflect baseline severity, so indiscriminate adjustment may create bias. Prospective research should prespecify causal diagrams and report exact adjustment sets. The surgical component remains essential. Adequate debridement, stable fixation, viable tissue and prompt soft-tissue coverage help control the biological environment of infection. A contemporary systematic review of open lower-limb fracture reconstruction found lower osteomyelitis risk associated with earlier flap coverage, although this cannot be used as an effect estimate for initial antibiotic timing [16]. Antibiotics do not compensate for inadequately treated devitalised tissue or delayed definitive coverage. Implications for care pathways The most actionable quality objective is early administration of an appropriate intravenous agent when an open fracture is suspected, without waiting for operating-room access, radiographs or transfer to a specialist unit. Clear triage triggers, stocked emergency-department antibiotics, prehospital pathways where appropriate, documentation of the first dose and transfer handoff are measurable interventions. Guideline recommendations vary for spectrum and duration by severity, underscoring the need to follow current institutional and specialist protocols rather than extrapolating timing studies into broad-spectrum escalation [17,18]. Evidence gaps and future studies A high-quality multicentre cohort should timestamp injury, first medical contact, first hospital and definitive-centre arrival separately. The antibiotic agent, intravenous dose, redosing and transfer sequence should be recorded prospectively. Outcome ascertainment should use consensus FRI definitions, distinguish deep SSI and osteomyelitis, and extend sufficiently beyond 90 days for late presentations. Analyses should evaluate time as a continuous exposure, assess nonlinearity, report prespecified categories and address transfer-related selection and injury-severity confounding. Site-specific subgroups, especially type III tibia injuries, should be determined in advance. Broader orthopaedic-trauma evidence establishes important context rather than a second independent timing effect. Randomised antibiotic prophylaxis comparisons support the role of prophylaxis, whereas trials of antibiotic duration, irrigation and coverage evaluate different clinical decisions [21–25]. Contemporary consensus documents emphasise accurate fracture-related infection definitions, timely prehospital care and coordinated wound management [26–30]. Historical infection-risk studies also show that contamination and injury characteristics affect infection risk [31]. Limitations Observational cohorts vary in time zero, clinical severity, antibiotic regimens, infection definitions, follow-up and adjustment. Some reported infection outcomes do not specifically identify osteomyelitis, and the available studies cannot be pooled into a reliable universal short-delay effect. No prospective causal effect or validated biological threshold is claimed.

Early systemic antibiotic prophylaxis should remain a priority in the management of open fractures. Some observational studies link delayed dosing to deeper infection, particularly for severe tibial injuries or very prolonged delays, while others show no significant association at 60–180 minutes. The evidence does not establish a universal safe delay or a distinct threshold at which osteomyelitis risk increases. Future studies must separate time origins, standardise deep infection and osteomyelitis definitions, and account for fracture severity and definitive orthoplastic care.

1. Gustilo RB, Anderson JT. Prevention of infection in the treatment of one thousand and twenty-five open fractures of long bones: retrospective and prospective analyses. J Bone Joint Surg Am. 1976;58(4):453–458. PMID:773941. 2. Hoff WS, Bonadies JA, Cachecho R, Dorlac WC. East practice management guideline: update on prophylactic antibiotic use in open fractures. J Trauma. 2011;70(3):751–754. 3. Whitehouse MR, McDaid C, Kelly MB, Moran CG, Costa ML. The effect of timing of antibiotic delivery on infection rates related to open limb fractures: a systematic review. Emerg Med J. 2017;34(9):613–620. doi:10.1136/emermed-2016-205900. 4. Marchiori JGT, Nunes APF. Time until the start of antibiotic prophylaxis and the risk of open fracture infection: a systematic review. Acta Ortop Bras. 2024;32(2):e263176. doi:10.1590/1413-785220243202e263176. 5. Chan JKK, Aquilina AL, Lewis SR, Rodrigues JN, Griffin XL, Nanchahal J. Timing of antibiotic administration, wound debridement, and the stages of reconstructive surgery for open long bone fractures of the upper and lower limbs. Cochrane Database Syst Rev. 2022;4:CD013555. doi:10.1002/14651858.CD013555.pub2. 6. Metsemakers WJ, Morgenstern M, McNally MA, et al. Fracture-related infection: a consensus on definition from an international expert group. Injury. 2018;49(3):505–510. doi:10.1016/j.injury.2017.08.040. 7. Lack WD, Karunakar MA, Angerame MR, et al. Type III open tibia fractures: immediate antibiotic prophylaxis minimizes infection. J Orthop Trauma. 2015;29(1):1–6. doi:10.1097/BOT.0000000000000262. 8. Roddy E, Patterson JT, Kandemir U. Delay of antibiotic administration greater than 2 hours predicts surgical site infection in open fractures. Injury. 2020;51(9):1999–2003. doi:10.1016/j.injury.2020.04.031. 9. Okhuereigbe D, Raffetto M, Li V, et al. Association between timing of antibiotics and deep surgical site infection in Gustilo-Anderson type III open tibia fractures. J Orthop Trauma. 2025. doi:10.1097/BOT.0000000000002996. 10. Early prophylactic antibiotics effect on infection rate in blunt open fractures. 2026. PMID:42108467. https://pubmed.ncbi.nlm.nih.gov/42108467/. 11. Kock FW, Basson TR, Burger MC, Ferreira N. The effect of treatment delays on fracture-related infection in open tibia shaft fractures: a retrospective cohort study. Strategies Trauma Limb Reconstr. 2025;20(1):25–30. doi:10.5005/jp-journals-10080-1640. 12. Haile AM, Dagnaw B, Gebeyehu M, et al. Fracture-related infection in open long-bone fractures: a bicenter case-control study in a limited resource country. JB JS Open Access. 2025. doi:10.2106/JBJS.OA.25.00043. 13. Hendrickson SA, et al. Timing of antibiotics and deep infection following Gustilo type IIIB open tibial fractures. Injury. 2020;51(4):1086–1090. PMID:32164953. 14. Zuelzer WA, et al. Time to antibiotics and deep infection after open tibial fractures. J Orthop Trauma. 2021. See study data discussed in Nguyen et al. [15]. 15. Nguyen The Diep, Nguyen Minh Chau, Phan Thanh Nam, Tien Van Nguyen. Timing of first systemic antibiotic administration and risk of deep infection in adults with open long-bone fractures: a systematic review and threshold-specific evidence synthesis. J Clin Med. 2026;15(19):7689. doi:10.3390/jcm15197689. 16. Dehnadi S, et al. Timing of flap coverage in open fractures: a systematic review and meta-analysis. 2026. PMID:42164206. 17. Buckman SA, Forrester JD, Bessoff KE, et al. Surgical Infection Society guidelines: 2022 updated guidelines for antibiotic use in open extremity fractures. Surg Infect (Larchmt). 2022;23(9):817–828. doi:10.1089/sur.2022.206. 18. Eastern Association for the Surgery of Trauma. Open fractures, prophylactic antibiotic use in—update. Practice management guideline. 2011. https://www.east.org/education-resources/practice-management-guidelines/details/open-fractures-prophylactic-antibiotic-use-in-update. 19. Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372:n71. doi:10.1136/bmj.n71. 20. Campbell M, McKenzie JE, Sowden A, et al. Synthesis without meta-analysis (SWiM) in systematic reviews: reporting guideline. BMJ. 2020;368:l6890. doi:10.1136/bmj.l6890. 21. Dellinger EP, Caplan ES, Weaver LD, et al. Duration of preventive antibiotic administration for open extremity fractures. Arch Surg. 1988;123(3):333–339. doi:10.1001/archsurg.1988.01400270067010. 22. The FLOW Investigators. A trial of wound irrigation in the initial management of open fracture wounds. N Engl J Med. 2015;373(27):2629–2641. doi:10.1056/NEJMoa1508502. 23. Garner MR, Sethuraman SA, Schade MA, Boateng H. Antibiotic prophylaxis in open fractures: evidence, evolving issues, and recommendations. J Am Acad Orthop Surg. 2020;28(8):309–315. doi:10.5435/JAAOS-D-18-00193. 24. Effects of antibiotic prophylaxis in patients with open fracture of the extremities: a systematic review of randomized controlled trials. J Orthop Trauma. 2016. PMID:27490013. 25. Where are we in 2022? A summary of 11,000 open tibia fractures over 4 decades. J Orthop Trauma. 2023. PMID:36952593. 26. Depypere M, Kuehl R, Metsemakers WJ, et al. Recommendations for systemic antimicrobial therapy in fracture-related infection: a consensus from an international expert group. J Orthop Trauma. 2020;34(1):30–41. doi:10.1097/BOT.0000000000001626. 27. Govaert GAM, Kuehl R, Atkins BL, et al. Diagnosing fracture-related infection: current concepts and recommendations. J Orthop Trauma. 2020;34(1):8–17. doi:10.1097/BOT.0000000000001614. 28. Prehospital antibiotic administration for suspected open fractures: joint COT/OTA/ACEP/NAEMSP/NAEMT position statement. Prehosp Emerg Care. 2024;28(8):1063–1067. doi:10.1080/10903127.2024.2409380. 29. General treatment principles for fracture-related infection: recommendations from an international expert group. Arch Orthop Trauma Surg. 2020. PMCID:PMC7351827. 30. Open fractures: evidence-based best practices. OTA Int. 2024. PMID:38708043. 31. Dellinger EP, Miller SD, Wertz MJ, Grypma M, Droppert B, Anderson PA. Risk of infection after open fracture of the arm or leg. Arch Surg. 1988;123(11):1320–1327. doi:10.1001/archsurg.1988.01400350034004.