Open fractures expose bone and deep soft tissues to environmental contamination. Subsequent infection reflects a multifactorial interaction among the extent of soft-tissue injury, vascular compromise, microbial contamination, fracture stabilization, debridement, and timing of definitive closure. Antibiotics are essential prophylaxis, but a clinically meaningful analysis must distinguish when the first systemic dose was actually delivered from when an injury was recognized or a transfer was completed [1–4]. Historical evidence linked early antibiotic treatment with lower infection risk, including 77 infections in 1,104 open fracture wounds reported by Patzakis and Wilkins [1]. Contemporary trauma pathways have increasingly used a first-dose target of approximately 60 minutes. Nevertheless, an operational target may differ from a biological time threshold; the latter requires comparison of otherwise similar injuries with a consistent time origin and sufficiently long follow-up [5–9]. FRI is not synonymous with erythema or superficial surgical-site infection. International consensus criteria use findings such as a sinus communicating with bone or implant, frank purulence, matching microorganisms in multiple deep samples, or histopathological identification of microorganisms as confirmatory evidence. Osteomyelitis is a clinically important subset of deep bone infection but is rarely reported separately in timing studies [10–12]. This review examines associations between first-dose timing and deep infection after open fractures, with attention to whether the interval begins at injury or hospital presentation, the magnitude of treatment delay, and subsequent fracture stabilization and soft-tissue coverage.

Review design and evidence identification The literature search covered open fractures, open tibial fractures, antibiotic initiation, time to antibiotics, antimicrobial prophylaxis, deep infection, osteomyelitis, surgical-site infection and fracture-related infection. Searches and reference screening considered PubMed/MEDLINE, Embase, Web of Science, the Cochrane Library and additional sources through August 2026. The available study-level reports were reviewed for relevant antibiotic-timing and infection outcomes. Eligibility and outcome framework Primary evidence comprised human observational studies of open limb fractures that reported the timing of an initial systemic antibiotic dose and infection or FRI outcomes. Injury-based and hospital-arrival-based intervals were analyzed separately. Studies of administrative treatment timeliness, antibiotic duration, debridement, or orthoplastic reconstruction were considered contextual rather than interchangeable first-dose effect estimates. Primary outcomes were confirmed FRI, deep SSI, and osteomyelitis; superficial SSI, mixed SSI/osteomyelitis composites, and unplanned debridement were treated as separate endpoints. Extraction and analytical strategy Study-level extraction included anatomical site, Gustilo–Anderson grade, sample size, timing origin, early/delayed cutoff, outcome definition, follow-up, adjusted and unadjusted estimates, and co-interventions. Odds ratios, regression coefficients, and hazard ratios were not converted into a shared measure. Studies were grouped by injury-to-first-dose time, hospital presentation-to-first-dose time, and intervals of several hours or more. No common pooled estimate was calculated because of major differences in injury severity, time origin, eligibility, and surveillance windows [5,9,13]. Methodological appraisal The methodological appraisal considered confounding by injury severity, transfer-related delays, prehospital antibiotic administration, accuracy of administration timestamps, antibiotic spectrum, timing of debridement and soft-tissue coverage, infection definitions and length of follow-up. Risk of bias was assessed narratively.

Study selection identified 2,342 records, comprising 2,318 database records (PubMed 756, Embase 682, Web of Science 460 and Cochrane Library 420) and 24 records from other sources. Following removal of 361 duplicates, 1,981 titles and abstracts were screened; 1,888 records were excluded. Of 93 full-text reports assessed, 78 were excluded: absence of an early–delayed antibiotic comparison (28), lack of deep surgical-site infection or osteomyelitis outcomes (22), unclear antibiotic timing (17), overlapping cohorts (6) and other reasons (5). Fifteen studies were classified as included (Figure 1). Antibiotic timing and deep infection in clinical cohorts The primary studies exposed inconsistent apparent thresholds. Lack et al. observed 137 Gustilo grade III open tibial fractures and found that antibiotic initiation more than 66 minutes after injury was associated with 90-day deep infection after adjustment (OR 3.78, 95% CI 1.16–12.31). In the same cohort, wound coverage beyond five days was associated with infection (OR 7.39, 95% CI 2.33–23.45), indicating two independent treatment-pathway intervals [2]. In a separate cohort of 127 analyzed open tibial injuries undergoing primary closure, Zuelzer et al. reported deep infection in 8 of 41 (20%) patients past a data-derived 150-minute threshold compared with 3 of 86 (approximately 4%) receiving antibiotics earlier (reported OR 5.60, 95% CI 1.40–22.20). The statistical signal was linked to the selected closure population, and a threshold identified after observing the data is not equivalent to a prospectively validated one [14]. Roddy et al. studied 230 open fracture patients; 10% experienced an SSI. Median antibiotic administration was 61 minutes (IQR 33–107) in patients without SSI and 83 minutes (IQR 40–186) among those with SSI. Administration after a 120-minute emergency-department threshold was associated with a reported adjusted hazard of 2.4 (P = 0.036), although the endpoint combined infections that may not represent confirmed bone infection [15]. In contrast, the 2025 Okhuereigbe cohort of 191 severe open tibial fracture patients reported an adjusted OR of 1.02 (95% CI 0.39–2.68) for delay beyond 60 minutes after emergency-department arrival and 1.08 (95% CI 0.35–3.37) for a three-hour comparison. Neither estimate established a significant association; both confidence intervals were broad [16,17]. Table 1. Contrasting first-dose timing findings in primary open-fracture cohorts Study Population Timing comparison Infection finding Lack 2015 [2] 137 type III open tibiae >66 min after injury Adjusted OR 3.78 (1.16–12.31), deep infection Zuelzer 2021 [14] 127 analyzed tibial fractures >150 min; derived cutoff 8/41 vs 3/86 deep infection; OR 5.60 (1.40–22.20) Roddy 2020 [15] 230 open fractures >120 min after ED presentation Adjusted hazard 2.4; P = 0.036; SSI Okhuereigbe 2025 [16] 191 type III open tibiae >60 min or >180 min from ED Adjusted OR 1.02 (0.39–2.68) and 1.08 (0.35–3.37) Grigorian 2023 [18] 3,367 lower-limb injuries ≤60 vs >60 min after arrival Adjusted composite SSI/osteomyelitis: P = 0.087 Morgan 2026 [19] 477 blunt long-bone fractures ≤60 vs >60 min after arrival Deep infection 12.6% vs 14.1%; P = 0.651 Haile 2025 [20] 84 FRI cases; 168 controls <3 h, 3–12 h, >12 h after injury >12 h associated with FRI; 3–12 h not significant Injury-based versus arrival-based antibiotic intervals Large arrival-based cohorts did not reproduce the magnitude of the injury-based estimates. In a national analysis of 3,367 surgically treated open femur/tibia fractures, Grigorian et al. reported that 2,400 patients (70.4%) received antibiotics within one hour of arrival. Crude infection rates were 1.1% versus 0.2% for the early and later groups (P = 0.011); after adjustment for injury severity and clinical covariates, an association with the SSI/osteomyelitis composite was not significant (P = 0.087). This difference between crude and adjusted analyses strongly suggests confounding related to the triage of severe injuries [18]. Morgan et al. compared 270 patients treated within one hour of arrival with 207 treated later. Deep infection occurred in 34/270 (12.6%) and 29/207 (14.1%), respectively (P = 0.651). The lower-limb deep infection frequency was higher than that for the upper limb (16.6% versus 5.6%; P = 0.001), illustrating the importance of anatomical site alongside antibiotic timing [19]. A separate prospective observational cohort of 736 individuals reported a 6% fracture-level deep infection rate, and multivariable analyses did not identify an independent association with time to antibiotics (OR 1.0, 95% CI 0.90–1.05). Gustilo grade and tibia/fibula involvement showed stronger relations to infection. Because the study measured a different clinical question and interval, it cannot negate signals detected in smaller severe-tibia cohorts [21]. Prolonged delays and orthoplastic treatment In a bicenter case-control study from Ethiopia, 706 cases were reviewed, with 84 FRI cases and 168 controls selected for analysis. Antibiotics were initiated later than three hours for 77.4% of the analyzed patients. Delays exceeding 12 hours were associated with FRI in multivariable analysis (reported adjusted OR 4.92; 95% CI 1.63–16.90), whereas a three-to-12-hour interval did not show a statistically significant association. This identifies a clinically distinct long-delay exposure rather than a minor breach of a 60-minute quality target [20]. Kock et al. evaluated 227 patients with 237 open tibial shaft fractures. Their principal positive associations concerned definitive stabilization later than five days (OR 4.7, 95% CI 2.0–10.9), soft-tissue reconstruction later than five days (OR 4.7, 95% CI 2.0–11.0), and more than two formal debridements (OR 15.6, 95% CI 5.8–41.6). These findings must not be reinterpreted as causal antibiotic-delay effects; they suggest that the overall injury-care pathway determines the subsequent infection burden [22]. The interaction between systemic prophylaxis and coverage timing was apparent in Lack et al.: deep infection was observed in 1/36 (2.8%) patients receiving both early antibiotics and early coverage, compared with 6/59 (10.2%) with a delay in either factor and 17/42 (40.5%) with both delayed. These are observed subgroup outcomes, not results of randomized treatment assignment [2]. Osteomyelitis outcomes Direct osteomyelitis-specific comparisons are less common than mixed infection endpoints. The Grigorian national database study combined surgical-site infection with osteomyelitis and captured inpatient events, potentially missing later bone infection [18]. Other studies reported deep SSI, repeated debridement, or FRI based on consensus clinical features. Accordingly, an overall “osteomyelitis risk ratio” cannot be inferred from these heterogeneous definitions. Consensus FRI diagnosis is particularly useful for future studies because deep culture, operative findings and late surveillance help distinguish persistent infection from superficial postoperative changes [10–12]. Table 2. Treatment-process findings relevant to infection interpretation Evidence Numerical finding Implication Patzakis & Wilkins [1] 77 infections in 1,104 open fracture wounds Historical benefit of early appropriate antibiotics Lack et al. [2] 1/36, 6/59, 17/42 infections across combined early/delayed antibiotic and coverage categories Timing of coverage modifies the treatment pathway National timing audit [23] 65,552 patients; 47.6% treated within 1 h; 74.2% within 4 h Timeliness performance, not infection effect Kock et al. [22] After 5 days: fixation OR 4.7; coverage OR 4.7 Reconstruction timing is a separate predictor Morgan et al. [19] Lower- vs upper-limb deep infection 16.6% vs 5.6% Fracture site is a major risk dimension Haile et al. [20] 84 cases, 168 controls; >12-h exposure aOR 4.92 Extreme delay is a different exposure from >60 min Interpretation of potential bias Confounding by indication is especially consequential: patients with severe soft-tissue injury may receive immediate treatment precisely because clinicians recognize a high baseline risk of infection. Conversely, patients requiring transfer may appear to have a short “arrival-to-dose” interval at a receiving hospital despite a much longer injury-to-treatment interval. The first dose, rather than a subsequent dose, is the relevant event. Missing transfer records, inability to verify actual administration rather than prescription, and inconsistent time zones in electronic records introduce further classification error [5,18,23]. Long-term FRI surveillance also matters. Some cohorts capture infection during the index admission or up to 30–90 days, whereas osteomyelitis and implant-associated infection may be recognized months later. This creates differential underascertainment even when antibiotic timing is accurately recorded. Comparability additionally depends on fracture grade, mechanism of injury, bacterial spectrum, local prophylaxis policy, vascular injury, and timing of debridement and flap coverage [10–12,24–26].

Summary of associations This synthesis distinguishes three clinically different observations. First, there is credible evidence for preventing long untreated intervals: case-control data indicate an association between delays beyond 12 hours and confirmed FRI. Second, evidence at one- and two-hour cutoffs is mixed, with injury-based severe-tibia studies showing risk elevations while larger hospital-arrival cohorts report weak or null adjusted associations. Third, reconstruction and wound-coverage timing are strong correlates of infection that should not be obscured by a sole focus on antibiotic timing [2,14–22]. Interpretation of antibiotic-timing thresholds A 60-minute benchmark can support prompt medication delivery and system audit, but the available cohorts do not identify a reproducible abrupt biological change at exactly one hour. Injury-to-first-dose and arrival-to-first-dose are not equivalent. Furthermore, a regression threshold derived from a single dataset, such as 66 or 150 minutes, may maximize separation in that sample without reproducing in another setting [2,14]. Quality-improvement targets should be evaluated separately from claims of causal risk thresholds. Clinical implications Evidence from randomised comparisons supports systemic prophylaxis to prevent infection, but questions about antibiotic type and duration differ from the injury-to-first-dose timing question [31,32,35]. Orthoplastic and trauma guidance prioritises early administration alongside coordinated wound debridement, skeletal stabilization and soft-tissue coverage [33,34,36–40]. These recommendations provide clinical context rather than additional independent estimates of a timing threshold. Nothing in these findings supports intentional postponement of indicated prophylaxis. Antibiotics should be delivered promptly as part of a coordinated open-fracture pathway, with attention to wound contamination, injury severity, debridement, fixation, and appropriate soft-tissue reconstruction. Care should be taken not to confuse the interval to first dose with antibiotic duration or spectrum, which are separate decisions addressed in contemporary surgical-infection guidelines [25]. Capturing injury time, all transfer points, first medication administration, fracture classification, and coverage time would permit meaningful audit and future causal analysis. Priorities for future research Future multicentre cohorts should prospectively timestamp injury, first medical contact, first hospital arrival, first systemic dose and transfer. Analysis should model antibiotic delay continuously as well as in prespecified groups, avoid selecting thresholds solely by receiver-operator analysis, adjust for contamination and vascular injury, and use a common FRI definition with at least 12-month ascertainment when feasible. Osteomyelitis should be identified separately from superficial SSI and unplanned irrigation and debridement. Target-trial emulation and carefully specified sensitivity analyses may help overcome some limitations of conventional retrospective comparisons. Limitations Variability in fracture grade, infection definitions, timing origins, antibiotic selection and observation periods limits comparisons. Some reports combined superficial SSI with deep infection or osteomyelitis, and estimates arose from largely observational designs susceptible to residual confounding. Because of these differences, a pooled causal effect was not calculated.

Prompt systemic antibiotic administration remains a core component of open-fracture management. Published cohorts suggest that markedly prolonged delays may increase the risk of FRI, while evidence for a universal one-hour deep-infection threshold is inconsistent. The strongest clinical interpretation incorporates injury severity, anatomical site, transfer status, and the timing of definitive skeletal and soft-tissue reconstruction. Osteomyelitis-specific longitudinal studies are needed before making outcome-specific causal claims.

1. Patzakis MJ, Wilkins J. Factors influencing infection rate in open fracture wounds. Clin Orthop Relat Res. 1989;(243):36–40. PMID:2721073. 2. 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. 3. Court-Brown CM, Bugler KE, Clement ND, et al. The epidemiology of open fractures in adults: a 15-year review. Injury. 2012;43(6):891–897. doi:10.1016/j.injury.2011.12.007. 4. Patzakis MJ, Harvey JP Jr, Ivler D. The role of antibiotics in the management of open fractures. J Bone Joint Surg Am. 1974;56:532–541. 5. Nguyen The D, Nguyen Minh C, Phan Thanh N, Nguyen TV. 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. 6. 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. 7. Hendrickson SA, Donovan R, Harries L, et al. Time to intravenous antibiotic administration (TIbiA) in severe open tibial fractures: impact of change to national guidance. Injury. 2020;51(4):1086–1090. doi:10.1016/j.injury.2020.03.005. 8. Dellinger EP, Caplan ES, Weaver LD, et al. Duration of preventive antibiotic administration for open extremity fractures. Arch Surg. 1988;123:333–339. 9. Patzakis MJ, Wilkins J, Moore TM. Considerations in reducing the infection rate in open tibial fractures. Clin Orthop Relat Res. 1983;(178):36–41. PMID:6883867. 10. 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. 11. McNally M, Govaert G, Dudareva M, Morgenstern M, Metsemakers WJ. Definition and diagnosis of fracture-related infection. EFORT Open Rev. 2020;5(10):614–619. doi:10.1302/2058-5241.5.190072. 12. Onsea J, Van Lieshout EMM, Zalavras C, et al. Validation of the diagnostic criteria of the consensus definition of fracture-related infection. Injury. 2022;53(6):1867–1879. doi:10.1016/j.injury.2022.03.024. 13. 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. 14. Zuelzer DA, Hayes CB, Hautala GS, et al. Early antibiotic administration is associated with a reduced infection risk when combined with primary wound closure in patients with open tibia fractures. Clin Orthop Relat Res. 2021;479(3):613–619. doi:10.1097/CORR.0000000000001507. 15. Roddy E, et al. Delay of antibiotic administration greater than 2 hours predicts surgical site infection in open fractures. Injury. 2020. PMID:32482427. 16. 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. 17. Fimmel FA, Rheaume EM, Falcone KS, et al. Improving time to antibiotic administration in open fractures. Pediatr Qual Saf. 2026;11(4):e890. doi:10.1097/pq9.0000000000000890. 18. Grigorian A, et al. Antibiotic administration within 1 hour for open lower extremity fractures is not associated with decreased risk of infection. 2023. PMID:36345122. 19. Morgan D, Orie G, Jones C, et al. Early prophylactic antibiotics effect on infection rate in blunt open fractures. J Orthop Surg Res. 2026;21:404. doi:10.1186/s13018-026-06926-w. 20. 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;10(2):e25.00043. doi:10.2106/JBJS.OA.25.00043. 21. Pollak AN, Jones AL, Castillo RC, et al. Time to initial operative treatment following open fracture does not impact development of deep infection: a prospective cohort study of 736 subjects. J Orthop Trauma. 2014. PMID:25050748. 22. 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. 23. State of the Union: Timeliness to Antibiotics in Open Fractures. 2024. PubMed Central: PMC11497909. 24. Declercq P, Zalavras C, Nijssen A, et al. Impact of duration of perioperative antibiotic prophylaxis on development of fracture-related infection in open fractures. Arch Orthop Trauma Surg. 2021;141(2):235–243. doi:10.1007/s00402-020-03474-8. 25. Surgical Infection Society Guidelines: 2022 updated guidelines for antibiotic use in open extremity fractures. Surg Infect (Larchmt). 2022. PMID:36350736. 26. Dehnadi S, et al. Timing of flap coverage in open fractures: a systematic review and meta-analysis. 2026. PMID:42164206. 27. Hak DJ. The infected fracture: can we agree on standard definitions? OTA Int. 2020;3(1):e057. doi:10.1097/OI9.0000000000000057. 28. Metsemakers WJ, Kortram K, Morgenstern M, et al. Definition of infection after fracture fixation: a systematic review of randomized controlled trials to evaluate current practice. Injury. 2018;49(3):497–504. doi:10.1016/j.injury.2017.02.010. 29. 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. 30. Factors influencing infection rates after open fractures of the radius and/or ulna. 2014. PMID:24674609. 31. Klifto KM, Klifto CS, Mithani SK, Mundy LR, Gage MJ, Della Rocca GJ. Evidence for systemic perioperative antibiotic prophylaxis for prevention of fracture-related infections following open fractures: systematic review and meta-analysis of randomized, controlled, clinical trials. J Am Acad Orthop Surg. 2026;34(4):e536–e554. doi:10.5435/JAAOS-D-24-00961. 32. Chang Y, Kennedy SA, Bhandari M, et al. Effects of antibiotic prophylaxis in patients with open fracture of the extremities: a systematic review of randomized controlled trials. JBJS Rev. 2015;3(6):e2. doi:10.2106/JBJS.RVW.N.00088. 33. British Orthopaedic Association. BOAST: Open Fractures. London: British Orthopaedic Association; 2017. https://www.boa.ac.uk/resource/boast-4-pdf.html. 34. American Association for the Surgery of Trauma Critical Care Committee. Antibiotic prophylaxis in injury: a clinical consensus document. Trauma Surg Acute Care Open. 2024;9:e001304. https://tsaco.bmj.com/content/9/1/e001304. 35. Gosselin RA, Roberts I, Gillespie WJ. Antibiotics for preventing infection in open limb fractures. Cochrane Database Syst Rev. 2004;(1):CD003764. doi:10.1002/14651858.CD003764.pub2. 36. Jaeger M, Maier D, Kern WV, Südkamp NP. Antibiotics in trauma and orthopedic surgery—a primer of evidence-based recommendations. Injury. 2006;37 Suppl 2:S74–S80. doi:10.1016/j.injury.2006.04.012. 37. 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. 38. 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. 39. 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. 40. 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.