Surgical Infection Society Guidelines: 2022 Updated Guidelines for Antibiotic Use in Open Extremity Fractures

Abstract

Background:

Open fractures, defined as fractures communicating with the environment through a skin wound, cause substantial morbidity after traumatic injury. Current evidence supports administration of prophylactic systemic antibiotic agents to patients with open extremity fractures to decrease infectious complications.

Methods:

The Therapeutic and Guidelines Committee of The Surgical Infection Society convened to revise guidelines for antibiotic use in open fractures. PubMed was queried for pertinent studies. Evaluation of the published evidence was performed using the GRADE framework. All committee members voted to accept or reject each recommendation.

Results:

In type I or II open extremity fractures, we recommend against administration of extended-spectrum antibiotic coverage compared with gram-positive coverage alone to decrease infections complications, hospital length of stay or mortality. In type III open extremity fractures, we recommend antibiotic therapy for no more than 24 hrs after injury, in the absence of clinical signs of active infection, to decrease infectious complications, hospital length of stay or mortality, and we recommend against extended antimicrobial coverage beyond gram-positive organisms to decrease infectious complications, hospital length of stay or mortality. In type III open extremity fractures with associated bone loss, we recommend antibiotic therapy in addition to systemic therapy to decrease infectious complications.

Conclusions:

Open fractures, defined as fractures communicating with the environment through a skin wound, cause substantial morbidity after traumatic injury. In 1976, Gustilo and Anderson¹ described a classification system for open fractures based on laceration size, presence and degree of tissue damage, wound contamination, and vascular injury. In 1984, these guidelines were revised to divide the most serious type III open fractures into subtypes to account for their high incidence of skin and soft tissue infection (Table 1).² Current infection rates range from 0%–2% for type I injuries, 2%–10% for type II, and up to 20%–25% for type III open fractures.^1,3,4 These injuries may develop deeper infections and chronic osteomyelitis, resulting in additional morbidity including neurovascular injury, fracture non-union, loss of mobility, and ultimately amputation.

Table 1.

Gustilo Classification of Open Fractures²

Type I	Open fracture with wound <1 cm in length and clean
Type II	Open fracture with laceration >1 cm long without extensive soft-tissue damage, flaps, or avulsions
Type IIIA	Adequate soft-tissue coverage of a fractured bone despite extensive soft-tissue laceration or flaps, or high-energy trauma irrespective of the size of the wound
Type IIIB	Extensive soft-tissue injury loss with periosteal stripping and bone exposure
Type IIIC	Open fracture associated with arterial injury requiring repair

The seminal prospective, randomized study by Patzakis et al.⁵ in 1974 reinforced that most infections after open extremity fractures result from gram-positive organisms. The study also ushered in the use of first-generation cephalosporins to prevent infections. Current evidence supports administration of prophylactic systemic antibiotic agents to patients with open extremity fractures to decrease infectious complications.^6,7 Although clinical studies have attempted to identify optimal systemic and local antimicrobial regimens, the most appropriate agents and durations of therapy for different fracture types remain unclear.

In 2006, Hauser et al.⁸ published the Surgical Infection Society guideline for prophylactic antibiotic use in open fractures. The authors' primary conclusion was that a short course of first-generation cephalosporins, initiated as soon as possible after injury, significantly reduces the risk of infection when combined with expeditious orthopedic fracture management. The authors reported insufficient evidence to support other clinical practices, including prolonged courses of antibiotic agents, extended antimicrobial coverage including gram-negative bacilli or clostridial species, or administration of local therapies including antibiotic beads. To update the original guideline and provide additional recommendations to address these clinical practices, the Therapeutics and Guidelines Committee of the Surgical Infection Society reviewed and evaluated more recent scientific evidence in the literature.

Objectives

Our population, intervention, comparator, and outcome (PICO) questions are as follows:

Population: Adult patients (>18 of age) with open long bone extremity fractures after traumatic injury. Combat-related injuries were excluded.

Intervention: Administration of antibiotic agents.

Comparator: Type I or II open fractures with extended spectrum antibiotic prophylaxis. Type III open fractures with extended spectrum antibiotic prophylaxis or prolonged duration of prophylaxis versus combined prophylactic antibiotic therapy, or addition of local prophylactic antibiotic therapy.

Outcomes: Infectious complications, hospital length of stay, or mortality.

PICO Question #1: In adult patients with Gustilo-Anderson type I or II open extremity fractures, does antibiotic prophylaxis beyond gram-positive coverage versus gram-positive coverage alone decrease infectious complications, hospital length of stay, or mortality?

PICO Question #2: In adult patients with type III open extremity fractures, does prolonged duration of antibiotic prophylaxis or extended antimicrobial coverage beyond gram-positive organisms decrease infectious complications, hospital length of stay, or mortality?

PICO Question #3: In adult patients with type III open extremity fractures, does local prophylactic antibiotic therapy combined with systemic antibiotic administration decrease infectious complications, hospital length of stay, or mortality?

Methods

Identification of references

A search of the PubMed database was performed independently by professional librarians and the study investigators from two institutions (Washington University School of Medicine in St. Louis and Zucker School of Medicine at Hofstra/Northwell) to identify all appropriate studies pertaining to the PICO questions. The following medical subject headings (MeSH) terms were utilized: open fractures, tibial fractures, femur fractures, humerus fractures, antibiotic agents, local antibiotic agents, cefazolin, ceftriaxone, clindamycin, gentamicin, tobramycin, aminoglycosides, vancomycin, penicillin, aztreonam, ciprofloxacin, piperacillin/tazobactam, prophylactic antibiotic agents, duration, mortality, hospital length of stay, infection, surgical site infection (SSI), wound infection, and amputation. Each PICO question had a separate search. Only English-language articles in patients >18 years old from 2006–2022 were included to follow-up from the previous SIS guideline.

After electronic literature search, all titles and abstracts were reviewed by two authors (S.A.B. and J.M.H.) to identify studies relevant to each PICO question. Case studies, animal studies, pediatric studies, and commentaries were excluded. Additional studies were identified by reviewing the bibliographies of the articles. In total, 229 studies were identified. After careful review and selection, a total of 26 articles were included in this review (Fig. 1).

FIG. 1.

Article search selection.

Data extraction and methodology

Grades of Recommendations, Assessment, Development, and Evaluation (GRADE) definitions were used to evaluate the quality and certainty of all reviewed studies. The GRADE framework was applied to all outcomes to assess for risk of bias, publication inconsistency, imprecision, and indirectness (Table 2).⁹ Using a process of iterative consensus, all study authors voted to accept or reject the recommendations.

Table 2.

GRADE Recommendations

Grade of recommendation/description	Benefit vs. risk and burdens	Methodologic quality of supporting evidence	Implications
1A/Strong recommendation, high-quality evidence	Benefits clearly outweigh risk and burden, or vice versa	RCTs without important limitations or overwhelming evidence from observational studies	Strong recommendation; can apply to most patients in most circumstances without reservation
1B/Strong recommendation, moderate-quality evidence	Benefits clearly outweigh risk and burdens or vice versa	RCTs with important limitations (inconsistent results, methodological flaws, indirect or imprecise) or exceptionally strong evidence from observational studies	Strong recommendation; can apply to most patients in most circumstances without reservation
1C/Strong recommendation, low-quality or very low-quality evidence	Benefits clearly outweigh risk and burdens or vice versa	Observational studies or case series	Strong recommendation but may change when higher quality evidence becomes available
2A/Weak recommendation, high-quality evidence	Benefits closely balanced with risks and burden	RCTs without important limitations or over-whelming evidence from observational studies	Weak recommendation; best action may differ depending on circumstances or patients' or societal values
2B/Weak recommendation, moderate-quality evidence	Benefits closely balanced with risks and burden	RCTs with important limitations (inconsistent results, methodological flaws, indirect, or imprecise) or exceptionally strong evidence from observational studies	Weak recommendation; best action may differ depending on circumstances or patients' or societal values
2C/Weak recommendation, low-quality or very low-quality evidence	Uncertainty in the estimates of benefits, risks, and burden; benefits, risk, and burden may be closely balanced	Observational studies or case series	Very weak recommendations; other alternatives may be equally reasonable

Adapted from Guyett et al.⁹

GRADE = Grades of Recommendations, Assessment, Development, and Evaluation; RCT = randomized controlled trial.

Results

PICO #1: In adult patients with Gustilo-Anderson type I or II open extremity fractures, does antibiotic prophylaxis beyond gram-positive coverage versus gram positive coverage alone decrease infectious complications, hospital length of stay, or mortality?

Most clinical practice guidelines recommend antibiotic coverage for gram-positive organisms in the setting of type I and II open fractures (Table 3).^10–13 There is no consensus on the optimal antibiotic regimen for these injuries or if gram-negative coverage is warranted.¹⁴ Moreover, studies recommending gram-positive coverage for type I and II fractures include multiple classes of antibiotic agents, including penicillins, cephalosporins, clindamycin, fluoroquinolones, and others. Considering that some classes maintain activity against gram-negative species, it is difficult to differentiate between strict gram-positive coverage versus additional coverage. Many studies date back 20–30 years, and evolving antibiotic resistance patterns may invalidate previous findings. Taken together, appropriate antibiotic selection may require ongoing re-evaluation.¹⁵ Since the previous 2006 guidelines, there are 2 articles that were used to formulate the updated recommendation, including 1 prospective study and 1 retrospective review

Table 3.

Articles Reviewed for PICO #1

Study	GRADE	Series/type
Haider (2013)¹⁶	1C	Prospective study
McMurtie et al. (2021)¹⁷	2C	Retrospective review

PICO = population, intervention, comparator, and outcome; GRADE = Grades of Recommendations, Assessment, Development, and Evaluation.

In 2013, Haider¹⁶ performed a prospective study evaluating 108 patients with open lower extremity fractures treated at a single center in Yemen between January 2007 and January 2010. No other inclusion or exclusion criteria were discussed. All fractures were irrigated and debrided in the operating room with subsequent wound closure following a standard protocol. All patients received ceftriaxone plus gentamicin for type I or II fractures, with metronidazole added for type III fractures, for a total of 7 to 10 days. The primary outcome was rate of infection. No pre-study power analysis was included.

The study cohort was 90% male with an average age of 28 years. The most common fracture sites were tibia (65%) and femur (33%). Injury mechanisms included motor vehicle collisions (37%), falls (18%), gunshot wounds (13%), motorcycle accidents (12%), industrial injuries (4%), and being struck by stones (2%). Of the 116 total fractures, 20 were type I (17%), 32 were type II (28%), and 64 were type III (47%). Ninety-six wounds were treated by primary closure (83%), and 72% were debrided within 6 hours. The author reported a total of 6 infections, all in patients with type III fractures. The follow-up period was not reported. Limitations of the study include its single-site, lack of a comparison group, and lack of criteria for diagnosis of infection. The author concluded intensive debridement and immediate fixation of fractures combined with primary closure and prolonged antibiotic use dramatically decreases infection rates in open extremity fractures.

In 2021, McMurtie et al.¹⁷ conducted a retrospective review of all type II open fractures in a level 1 trauma center over a 5-year period to determine outcomes of type II open fractures treated with gram-positive coverage only compared to broad-spectrum coverage. Prophylactic antibiotic agents were started on arrival to the emergency department based on the judgment of the house officer on call, with the final determination of the open fracture classification determined by the operating surgeon. Patients either received cefazolin (clindamycin if allergic to cephalosporins) or piperacillin-tazobactam. Antibiotic agents were continued for a minimum of 24 hours after surgical debridement.

One hundred forty-four patients were included: 74 patients receiving gram-positive coverage and 70 patients receiving broad-spectrum coverage. Between the 2 groups, there was no difference in age, gender, race, body mass index (BMI), smoking status, or American Society of Anesthesiologists physical status classification (ASA class). Groups varied by mechanism of injury, with the gram-positive group having a higher percentage of falls (26%) compared with the broad-spectrum coverage group who had a higher incidence of motor vehicle accident (65%). There was no difference between groups for hospital length of stay, fracture-related injury, onset of infection, or rates of polymicrobial infection. The authors concluded that for type II open fractures, there is no clear benefit to adding broad-spectrum coverage compared to gram-positive coverage alone.¹⁷

Strengths of this study include 1 of the first to evaluate the use of broad-spectrum antibiotic agents in type II open fractures, and also discovering a large cost difference between using broad-spectrum antibiotic agents compared with using cefazolin. Limitations of this study include the retrospective nature, a higher number of debridements in the broad-spectrum group, and a discrepancy in misclassifying a type II as a type III fracture.

Although nearly all clinical guidelines recommend limiting antibiotic coverage to only gram-positive organisms in type I and II open fractures, multiple challenges remain.^8,13 Many routine gram-positive antibiotic choices are, in fact, extended-spectrum therapies. Bacteria are demonstrating increasing resistance to antimicrobial agents. Many infections are polymicrobial in nature. Last, clinicians may not adhere to standardized clinical guidelines. Taken together, future studies should explore discrepancies between observed and expected microbial patterns and clinical practice trends to help determine a path forward in an era of improved antimicrobial stewardship and heightened attention to patient outcomes and overall health care quality.

Level 2C

PICO #2: In adult patients with type III open extremity fractures, does prolonged duration of therapy or extended antimicrobial coverage beyond gram-positive organisms decrease infectious complications, hospital length of stay, or mortality?

Since 2006, we identified 18 studies that address this question, including 1 prospective randomized study, 9 retrospective reviews, 4 systematic reviews, 3 retrospective cohort studies, and 1 retrospective case control study (Table 4). In 2010, Anderson et al.¹⁸ reviewed use of antibiotic agents in the management of open fractures to answer questions regarding antimicrobial selection, optimal timing of administration, and duration of administration. They discussed practical considerations and avoidance of potential pitfalls in the treatment of open fractures of the lower extremity, including avoidance of cultures immediately post-injury because of limited correlation of bacteria isolated with those causing infection (more likely nosocomial), ensuring an accurate allergy history reconciled with recommended agents, and obtaining accurate accounts leading to injury (e.g., farm/water) that may require additional antimicrobial therapy. Based largely on their review of previous guidelines,⁸ 2 systematic reviews,¹⁹ and 2 randomized controlled trials,^3,20 they concluded that prophylactic antibiotic agents for open fractures should be administered within 3 hours of injury, regardless of severity. Type I and II open fractures warrant use of first-generation cephalosporins with additional risk of gram-negative organisms in type III requiring addition of an aminoglycoside. They recommended continuing antibiotic agents for 48–72 hours, but no longer than 24 hours after wound closure. A strength of the study includes the clear overview of the topic, while a limitation includes the small number of studies included.

Table 4.

Articles Reviewed for PICO #2

Study	GRADE	Series/type
Anderson et al. (2011)¹⁸	1C	Retrospective review
Fletcher et al. (2007)¹⁹	1C	Systematic review
Barton et al. (2012)²¹	2C	Retrospective review
Chang et al. (2015)⁶	2C	Systematic review
Isaac et al. (2016)²²	2C	Systematic review
Messner et al. (2017)²³	2C	Systematic review
Janmohammadi et al. (2011)²⁴	2A	Prospective randomized study
Dunkel et al. (2013)²⁵	1C	Retrospective review
Pannell et al. (2014)²⁶	2C	Retrospective review
Tessier et al. (2016)²⁷	2C	Retrospective review
Rodriguez et al. (2014)²⁸	1C	Retrospective review
Olesen et al. (2015)²⁹	2C	Retrospective review
Redfern et al. (2016)³³	1C	Retrospective review
Zhu et al. (2017)³⁴	2C	Retrospective review
Bremmer et al. (2017)³⁵	2C	Retrospective review
Bankhead-Kendall et al. (2019)³⁶	2C	Retrospective review
Depcinski et al. (2019)³⁷	2C	Retrospective review
Shawar et al. (2020)³⁸	2C	Retrospective review

PICO = population, intervention, comparator, and outcome; GRADE = Grades of Recommendations, Assessment, Development, and Evaluation.

Studies suggest clinicians prescribe longer or more extended courses of antibiotic agents in patients with type III open fractures. In 2012, Barton et al.²¹ performed a retrospective analysis of adherence to the 1998 EAST antibiotic prophylaxis guideline in 214 patients with open extremity fractures admitted to a rural level 1 trauma center in Vermont between January 2004 and December 2008. The incidence of SSI in patients with type III fractures was 16%. Although all patients received antibiotic prophylaxis, only 18%, 10%, and 50% of type IIIA, IIIB, and IIIC fractures, respectively, were guideline compliant (gram-positive and gram-negative coverage for 3 days or 24 hours after definitive wound closure, whichever occurred first). Most non-compliance resulted from regimens exceeding recommended duration (71%) or coverage spectrum and duration (20%). Common regimens were cefazolin (47%) and gentamicin-cefazolin (36%). The authors found guideline non-compliance was associated with increased hospital and intensive care unit (ICU) length of stays, number of surgeries performed, and number of packed red blood cell units transfused. Although the findings suggest prolonged antibiotic therapy lead to worse outcomes, there was no direct relation between antibiotic duration and outcome.²¹

Multiple systematic reviews have investigated the optimal duration of prophylactic antibiotic therapy for open extremity fractures. In 2015, Chang et al.⁶ reviewed 1,104 patients from three studies and compared the effects of one day of antibiotic prophylaxis (first- or second-generation cephalosporins, or single-dose fluoroquinolone) with 3–5 days (first- or second-generation cephalosporins) in patients with open extremity fractures. The authors found no difference in infection rates (relative risk [RR], 0.97; 95% confidence interval [CI], 0.69–1.37; I² = 0%), but found a high risk for bias (allocation concealment, lack of blinding), resulting in an evidence quality rating of low to moderate. Subgroup analysis by fracture grade was not performed, as one study included only type I and II fractures.

In 2016, Isaac et al.²² identified eight studies published between 1950 and 2016 and concluded that there were no data to support prophylactic antibiotic courses longer than 24 hours to decrease risk of infection or improve clinical outcomes. In 2017, Messner et al.²³ evaluated 6,692 patients from 32 studies (five comparative and 27 observational) published between 1970 and 2017. The authors found no difference in infection rate between patients with open fractures receiving less than 72 hours of antibiotic agents versus those given courses longer than 72 hours. Subgroup analysis revealed no difference in outcomes in patients with all grades of open fractures receiving less than 24 hours of antibiotic agents versus those given more than 72 hours (943 patients from three studies, effect estimate, 0.91; 95% CI, 0.58–1.42). This finding extended to patients with type III fractures (134 patients from two studies, effect estimate, 1.19; 95% CI, 0.53–2.70).²³ These systematic reviews support short courses (≤24 hours) of prophylactic antibiotic agents in patients with type III open extremity fractures.

To evaluate extended antimicrobial coverage beyond gram-positive organisms, Janmohammdi et al.²⁴ conducted a prospective, randomized study in 2011 comparing prophylactic regimens of cefazolin plus gentamicin versus cefazolin plus ciprofloxacin for the management of type IIIA open fractures. Primary end points were rate of deep infection and efficacy of the regimen. The cefazolin plus gentamicin patients (group 1, n = 148) received 1 g cefazolin every 8 hours and gentamicin 5 mg/kg/d divided into 3 doses for 3 days. The cefazolin plus ciprofloxacin patients (group 2, n = 153) received 1 g cefazolin and ciprofloxacin 500 mg orally 3 times per day for 3 days. The authors found similar rates of deep infection in both groups (5% group 1 vs. 7% group 2). The efficacy of group 1 was 95% compared to 94% for group 2 (p = 0.68). They concluded ciprofloxacin may be used instead of an aminoglycoside in combination with a first-generation cephalosporin in management of type IIIA open fractures.²⁴ Although ciprofloxacin is an alternative to gentamicin, the use of fluoroquinolones is discouraged because of proposed negative effects on fracture healing and increasing bacterial resistance.¹³

In 2013, Dunkel et al.²⁵ published a single-center, retrospective study of 1,290 patients (median age, 41; interquartile range [IQR], 8–01; 78% male) with 1,492 extremity fractures presenting to a level 1 trauma center in Geneva, Switzerland, between January 1996 and December 2009. There were 310 type III fractures (63 [20%] IIIA, 53 [17%] IIIB, 63 [20%] IIIC). Patients received prophylactic antibiotic agents for a median of 3 days (IQR, 3–6 days). Infection, defined by presence of pus, need for surgical treatment, and prescription of additional antibiotic agents, was documented in 37 (12%) of fractures (2 [3%] IIIA, 3 [8%] IIIB, and 21 [33%] IIIC). Infection was more common in males (85%). Multivariable analysis did not show any benefit for antibiotic administration longer than 24 hours. Although cefuroxime (72% of cases) and amoxicillin-clavulanate (4% of cases) were used most commonly, no standard therapy was defined, and more than 40 different regimens were utilized. Although the population was relatively large and varied with respect to fracture location, none of the patients suffered blast injuries (gunshots or explosions), which may limit the generalizability of the findings.

In 2014, Pannell et al.²⁶ performed a retrospective analysis of all patients admitted with open fractures to determine if aminoglycoside administration leads to acute kidney injury. They included 159 patients, with 41 patients receiving cefazolin alone (group A) and 113 patients receiving cefazolin plus gentamicin (group B), including 46 with type III fractures. Comparing estimated glomerular filtration rate (eGFR) at admission and throughout the hospital stay, authors found both groups had increases in average eGFR over the first post-injury week (p < 0.008), but there was no difference in eGFR between groups. One patient in group B required continuous renal replacement therapy (CRRT) for 6 days, which potentially could have been avoided. There were 2 patients in group A (4.8%), and 5 patients in group B (4%) who developed acute kidney injury (p = 0.599). The authors concluded gentamicin does not increase the risk of kidney dysfunction. Similarly, in a single-center, retrospective review of 167 patients with open fractures, Tessier et al.²⁷ found no association between gentamicin and nephrotoxicity.

In 2014, Rodriguez et al.²⁸ performed a retrospective review of 174 patients with open lower extremity fractures admitted to a single level 1 trauma center between January 2006 and June 2010. Exclusion criteria included moribund patients and those managed at another institution for longer than 24 hours. A hospital protocol was initiated for treatment of open fractures based on fracture grade, which included early orthopedic consultation, standardized wound inspection and dressing application, tetanus prophylaxis, and specific prophylactic antibiotic regimens. Type I and II fractures received cefazolin for 48 hours or clindamycin for penicillin allergy. Type III fractures received ceftriaxone for 48 hours or clindamycin and aztreonam for penicillin allergy. In contrast to pre-protocol, no patients received aminoglycosides, vancomycin, or penicillin. The use of aminoglycosides and glycopeptides was non-compliant with the protocol. All patients underwent irrigation and debridement within 8 hours of injury. Surgical site infection was defined by clinical signs and symptoms with positive wound culture or treatment with broad-spectrum antibiotic agents.

Baseline demographics and characteristics including age, gender, mechanism of injury, and disposition were similar between pre-protocol and post-protocol cohorts. There were 101 pre-protocol and 73 post-protocol patients for analysis. Administration of glycopeptide and aminoglycoside antibiotic agents decreased after protocol initiation (53.5% vs. 16.4%; p = 0.0001). The combined SSI rates for pre-protocol (20.8%) and post-protocol patients (24.7%) were similar (p = 0.58). The SSI rate for type III open fractures was similar between pre- (29.7%) and post-protocol (40%) groups (p = 0.62). Limitations included the single site and retrospective design, small sample size and underpowered analysis for the type III fractures, variability in time and type of wound closure, potential incidence of concomitant injuries or poor interobserver reliability in assessing wound infection, and compliance with all aspects of the treatment protocol. The authors concluded implementation of a more narrow-spectrum antibiotic protocol for open fractures does not increase skin and soft tissue infection rates.

In 2015, Olesen et al.²⁹ performed a retrospective review evaluating patients who underwent free flap coverage of an open tibial fracture between 2002 and 2013 to identify risk factors for complications including amputation, infection, and non-union. Hospital length of stay or mortality were not studied. They reviewed organisms identified by culture from infected cases to assess appropriateness of empiric antibiotic prophylaxis. Overall, 56 patients met criteria, and 11 were excluded for missing records. Of the remaining 45 patients, approximately 71% had type III open fractures (26 type IIIB, 6 type IIIC) and 22 developed an infection. Type III open fractures accounted for 19 of 22 of infections. There were 43 bacterial species identified, with the majority caused by Enterococcus sp. and coagulase-negative staphylococcus. Gram-negative bacteria included Pseudomonas aeruginosa, other Pseudomonas, and Enterobacteriaceae. Other gram-negative bacteria without further genus provided may have been included in the miscellaneous and anaerobic bacteria classifications.²⁹

The authors describe cefuroxime and metronidazole for prophylaxis, noting this regimen only provided adequate coverage for 12 of 43 cases described. Of those, both meropenem and gentamicin covered all other gram-negative bacteria listed with exception of one Enterobacteriaceae and two other Pseudomonas isolates. Vancomycin had activity against all identified gram-positive bacteria. It is not clear which organisms were associated with type III fractures. The authors concluded that cefuroxime and metronidazole have limited coverage of bacteria related to infection in type III open fractures, and suggested vancomycin and meropenem be used as first line for prophylaxis.²⁹ There was, however, no comment on the duration of antibiotic use. Additional studies, however, have suggested that vancomycin is generally not needed for routine coverage of methicillin-resistant Staphylococcus aureus (MRSA) coverage in addition to gram-negative coverage. However, if the patient is at high risk of MRSA infection, or is a known nasal carrier, then it is not unreasonable to include it in the therapeutic regimen.^30–32

In 2016, Redfern et al.³³ performed a retrospective cohort study of 72 patients with type III open fractures admitted to a single level 1 trauma center between January 2004 and December 2012 comparing 2 antibiotic prophylaxis regimens. Exclusion criteria included isolated fractures distal to the radiocarpal or tibiotalar joints, death within 24 hours of admission, pre-injury antibiotic or immunosuppressant use, loss to follow-up within 1 year, amputation unrelated to infection, and use of non-study antibiotic agents. All patients received early prophylactic antibiotic administration and operative debridement within 6 to 8 hours if possible. Thirty-seven patients (51%) received cefazolin plus gentamicin and 35 (49%) received piperacillin-tazobactam. The primary outcome was SSI at 1 year. Secondary outcomes included SSI at 30 days, rates of non-union, mortality, and re-hospitalization at 1 year after injury. No pre-study power analysis was reported.

Baseline demographics and characteristics were similar between groups, except more males received piperacillin-tazobactam. Wound vacuum therapy was more common in the piperacillin-tazobactam group (40% vs. 24.3%), but not significantly so (p = 0.154). Overall, 1-year SSI rate was 32.4% in the cefazolin plus gentamicin group versus 31.4% in the piperacillin-tazobactam group (p = 1.0). There were no differences between groups for any secondary outcomes. Limitations include the retrospective design, reliance on International Classification of Diseases, Ninth Revision (ICD-9) coding for identifying injuries, variation in dead space management techniques (vacuum assisted closure [VAC] therapy), underpowered analysis based on the observed 1% difference in SSI rates, and possible variability in antibiotic dosing and timing of initial therapy. In addition, there was no comment about the duration of antibiotic use in either group.

In 2017, Zhu et al.³⁴ conducted a retrospective cohort study evaluating patients with open fractures exposed to seawater. During a 3-year period, there were 1,337 open fractures, of which 107 had seawater contamination and 43 of 107 were type III. Incidence of deep infection was higher in the seawater contamination group (15.2% vs. 5%; p = 0.03). In patients with cultures, there was no predominant organism. Sensitivity tests demonstrated imipenem, levofloxacin, and ciprofloxacin were most effective in treatment of seawater-contaminated wounds. The authors concluded imipenem is an appropriate antibiotic for treatment of infection in seawater-contaminated wounds, and for prophylaxis, a quinolone or cephalosporin is recommended.³⁴ There was no comment about the duration of antibiotic agents used for prophylaxis or treatment of deep infections.

In 2017, Bremmer et al.³⁵ performed a single-center, retrospective analysis to evaluate the clinical effectiveness of antimicrobial prophylaxis in adults with lower-extremity open fractures of the ankle, tibia, fibula, or femur. The primary end point was incidence of osteomyelitis within 12 months of injury. Secondary end points included time of antibiotic initiation and drug selection. Hospital length of stay and mortality were not reported. Patients who received antibiotic therapy for other than fracture prophylaxis or who had concomitant upper-extremity open fractures were excluded.³⁵

Overall, 31.3% of patients suffered type III fractures, and 88 patients (98%) received cefazolin prophylaxis. Additional gram-negative coverage was added in 59.3% (16/27) of patients with type III fractures. Gentamicin (n = 23) and tobramycin (n = 1) were the primary agents selected. Other agents included aztreonam (n = 3), ceftriaxone (n = 1), and piperacillin-tazobactam (n = 1). There was no difference in osteomyelitis rates in patients with type III fractures who did or did not receive gram-negative coverage (18.8% [3/16] vs. 0 [0/11]; p = 0.25). Of note, gram-negative organisms caused all type III fracture osteomyelitis cases (3/3) and all patients received additional gram-negative coverage. Time to antibiotic administration was shorter among patients who did not develop osteomyelitis, but the difference was not significant. The median antibiotic stop time after wound closure was 22.9 hours, and stop time was not different in patients who developed osteomyelitis and those who did not (median 23 hours vs. 22.9 hours; p = 0.7145). Limitations of the study include its single-center design, small sample size (60% of patients with open fractures excluded), and lack of power to demonstrate differences between type III fracture outcomes. The authors concluded osteomyelitis remains prevalent following open lower-extremity fractures despite recommended antimicrobial prophylaxis, and resistance patterns should be considered when administering prophylaxis.

In 2019, Bankhead-Kendall et al.³⁶ performed a retrospective review of 126 adult patients with type III lower extremity open fractures admitted to an urban level 1 trauma center between 2010 and 2015. No exclusion criteria were listed. The authors recorded Injury Severity Score (ISS), fracture location, fracture grade, type of antibiotic administered, and incidence of acute kidney injury (AKI), SSI, hardware removal, hospital length of stay, and disposition. Patients were classified into 2 groups based on whether they received a cephalosporin alone, or a cephalosporin plus aminoglycoside. Primary and secondary outcomes were not explicitly stated. No pre-study power analysis was reported.³⁶

Baseline demographics and characteristics were similar between groups. Average patient age was 47, 66% were male, and 55% were Caucasian. Most patients (88%) suffered blunt trauma resulting from motor vehicle collisions (57%) or falls (26%). There were 65 patients in the cephalosporin alone group and 61 in the cephalosporin plus aminoglycoside group. Neither mean duration of antibiotic administration (cephalosporin 66 hours vs. cephalosporin and aminoglycoside 72 hours; p = 0.4), nor incidence of other orthopedic injuries differed between groups. Overall, there were no differences in SSI, infectious-related hardware removal, length of stay, or disposition between groups. Patients in the cephalosporin + aminoglycoside group had higher incidence of AKI (10% vs. 4%; p < 0.05). Study limitations include its single-center retrospective design, small sample size, absence of type, dose, and frequency of antibiotic information, and missing power analysis. The authors concluded cephalosporins may be sufficient prophylaxis for type III open lower extremity fractures.

In 2019, Depcinski et al.³⁷ performed a retrospective study of patients receiving cefazolin alone versus cefazolin plus aminoglycoside for type III open fractures admitted to a level 1 trauma center between January 2010 and August 2014. The primary end point was type III open fracture-related infection rates within one year. Secondary end points included 30-day mortality, one-year re-admission secondary to a fracture complication, length of initial hospital stay, and type III fracture-related multi-drug–resistant (MDR) infection within one year. Patients were included if they had a type III open fracture of the upper or lower extremity or pelvis and received initial antibiotic prophylaxis with the study antibiotic agents. There were 68 patients, including 53 in the cefazolin monotherapy group and 15 in the cefazolin plus aminoglycoside group.³⁷

Baseline demographics were similar between groups, with diabetes mellitus being more prevalent in the combination group (2/15 [13.3%] vs. 0/52 [0%]; p = 0.047). Clinical characteristics were also similar except for length of antibiotic therapy after the initial operation, which was longer in the combination group (median, 2 days, [IQR, 2–2.5] vs. 1.5 days [IQR, 1–2]; p = 0.015). For the primary outcome, fewer patients developed a type III fracture-related infection within one year in the cefazolin only group compared with combination therapy (8/53 [15.1%] vs. 6/15 [40%]; p = 0.035). For the secondary outcomes, rates of fracture-related infection caused by MDR organisms was higher in the combination group (3/15 [20%] vs. 1/53 [1.9%]; p = 0.046). There were no differences in 30-day mortality, 1-year re-admission rates, or hospital length of stay. Study limitations include its retrospective design and inadequate power to assess cefazolin alone non-inferiority.

In 2020, Shawar et al.³⁸ conducted a retrospective cohort study of 85 patients (age >18) with type III open fractures admitted to a single level 1 academic medical center from January 2010 to December 2016 to compare composite adverse events in patients before and after a change in prophylactic antibiotic regimens. Exclusion criteria included death within 24 hours of admission, injuries requiring amputation, prisoners, patients receiving renal replacement therapy before admission, and patients who received both study antibiotic agents. All patients received early fracture evaluation, irrigation with saline or betadine or both, closed reduction, and splinting within the trauma bay. Antibiotic selection was based on fracture type according to Gustilo-Anderson classification. Ungraded fractures at admission were later graded via imaging and operative reports. Antibiotic agents included piperacillin-tazobactam (4.5 g, every 8 hours), cefazolin (2 g, every 8 hours), and tobramycin (7 mg/kg, hospital practice). Sixty-two patients received high-dose tobramycin plus cefazolin or clindamycin, and 23 received piperacillin-tazobactam. The primary outcome was rate of composite adverse events (AEs), including SSI, hospital re-admission with surgical intervention, and nephrotoxicity. Secondary outcomes included rate of SSI within 30–60 days after injury. A power analysis determined a sample size of 153 patients to detect a 5% decrease in the incidence of AEs with 80% power.³⁸

Baseline demographics and characteristics were similar between groups, except median hospital stay was longer in the piperacillin-tazobactam group, as was the number of immunocompromised patients. Overall, 85% of patients in both groups had 1 fracture, 72 fractures in the tobramycin group, and 26 in the piperacillin-tazobactam group. Most injuries affected the lower extremity and resulted from blunt trauma (83.6% in the tobramycin group and 85% in the piperacillin-tazobactam group). Median time from injury to antibiotic administration was shorter for the piperacillin-tazobactam group, 43.5 minutes in the piperacillin-tazobactam group compared with 62 minutes in the tobramycin group. More patients in the tobramycin group (89%) underwent operative intervention within the first 12 hours after injury compared with the piperacillin-tazobactam group (67%; p = 0.017). Overall, 32.3% of patients in the tobramycin group experienced at least one AE, versus 13% in the piperacillin-tazobactam group (p = 0.10). More patients in the tobramycin group experienced an SSI at 30 and 60 days, respectively. There were no differences between groups across the other secondary outcomes. Limitations of the study include its retrospective design, underpowered analysis, and long accrual period.

In type III open extremity fractures, we recommend antibiotic therapy for no more than 24 hours after injury, in the absence of clinical signs of active infection, to decrease infectious complications, hospital length of stay, or mortality.

Level 1C

In type III open extremity fractures, we recommend against extended antimicrobial coverage beyond gram-positive organisms to decrease infections complications, hospital length of stay, or mortality.

Level 2C

PICO #3: In adult patients with type III open extremity fractures, does local antibiotic therapy combined with systemic antibiotic administration decrease infectious complications, hospital length of stay, or mortality?

Higher infection rates after complex type III open extremity fractures may result from the inability of systemic antibiotic agents to reach sufficient tissue concentrations, potentially from disrupted vascular anatomy.⁷ Given the high infection rate with type III fractures, local antibiotic therapies in the form of antibiotic beads and spacers may be utilized along with adequate soft tissue coverage to reduce complications. Antibiotic beads and spacers can shape and mold the soft tissues in patients with segmental bone loss and may bypass the vascular deficiency increasing local tissue antibiotic concentrations.³⁹ In addition, when used with internal fixation, local antibiotic agents may reduce colonization and biofilm formation.⁴⁰

Since the 2006 guideline, we identified six studies addressing local antibiotic therapy in patients with type III open extremity fractures, including one retrospective cohort study, two retrospective case series, two retrospective reviews, and one meta-analysis (Table 5). In 2010, Hutson et al.⁴¹ conducted a retrospective review of 76 patients with type IIIB tibial fractures, of whom 38 underwent flap coverage. Eighteen patients (19 fractures) were treated using a protocol of debridement, half-pin external fixation, flap coverage over antibiotic-impregnated beads or spacers, and delayed bone reconstruction with circular tensioned wire external fixation and bone transport. Spacers consisted of dry cement with tobramycin powder and vancomycin. One patient had a post-operative infection with MRSA treated with intravenous vancomycin, while another patient developed an infected hematoma after removal of the antibiotic spacer. Of the 19 fractures, 12 healed with equal leg length while 7 developed moderate shortening. There was no information on hospital length of stay or mortality.⁴¹

Table 5.

Articles Reviewed for PICO #3

Study	GRADE	Series/type
Hutson et al. (2010)⁴¹	2C	Retrospective review
Chaudhary et al. (2011)⁴²	2C	Retrospective case series
Craig et al. (2014)⁴⁰	1C	Meta-analysis
Metsemakers et al. (2015)⁴³	2C	Retrospective case series
Lawing et al. (2015)⁴⁴	2C	Retrospective review
van Niekerk et al. (2017)⁴⁵	2C	Retrospective cohort study

PICO = population, intervention, comparator, and outcome; GRADE = Grades of Recommendations, Assessment, Development, and Evaluation.

Table 6.

Table of Recommendations

PICO question	Recommendation	Level of evidence
In adult patients with Gustilo-Anderson Type I or II open extremity fractures, does antibiotic therapy beyond gram positive coverage vs. gram positive coverage alone decrease infectious complications, hospital length of stay, or mortality?	In Type I or II open extremity fractures, we recommend against administration of extended-spectrum antibiotic coverage compared with gram-positive coverage alone to decrease infectious complications, hospital length of stay, or mortality.	2C
In adult patients with Type III open extremity fractures, does prolonged duration of therapy or extended antimicrobial coverage beyond gram-positive organisms decrease infectious complications, hospital length of stay, or mortality?	In Type III open extremity fractures, we recommend antibiotic therapy for no more than 24 hours after injury, in the absence of clinical signs of active infection, to decrease infectious complications, hospital length of stay, or mortality.	1C
	In Type III open extremity fractures, we recommend against extended antimicrobial coverage beyond gram-positive organisms to decrease infectious complications, hospital length of stay, or mortality.	2C
In adult patients with Type III open extremity fractures, does local antibiotic therapy in addition to systemic antibiotic administration decrease infectious complications, hospital length of stay, or mortality?	In Type III open extremity fractures with associated bone loss, we recommend administration of local antibiotic therapy in addition to systemic therapy to decrease infectious complications. Additional data are needed to determine if there are benefits to patients in terms of decreased hospital length of stay or mortality.	2C

PICO = population, intervention, comparator, and outcome

Antibiotic-impregnated collagen sponges have been used in combination with systemic antibiotic agents to reduce deep infections and improve bone union in open fractures. In 2011, Chaudhary et al.⁴² studied 35 patients with open type IIIA fractures who had gentamicin-impregnated collagen sponges placed near the implant and exposed bone. They did follow-up wound checks on day 4, in addition to measuring C-reactive protein and erythrocyte sedimentation rates post-operatively to three weeks. Three patients (9.67%) were diagnosed with local wound complications of superficial infection and skin loss, and 2 patients (6.45%) developed deep infections that improved after repeat debridement and local antibiotic sponge application. Delayed union was found in 5 patients (16.13%). The authors found that local antibiotic-impregnated collagen sponges in combination with systemic antibiotic agents for 3 to 5 days were promising in patients with type IIIA open fractures.⁴²

In 2014, Craig et al.⁴⁰ conducted a meta-analysis comparing deep wound infections in patients with open tibial fractures treated with adjunctive locally delivered antibiotic agents compared with standard care of systemic antibiotic agents only. They included 14 studies examining systemic antibiotic agents only, and 7 studies examining adjunctive locally administered antibiotic agents peri-operatively at the tissue-implant interface. They found absolute rates of infection were lower for all types of open fractures using systemic and locally administered antibiotic agents in combination. For patients with severe type III open fractures, the authors found the infection rate when only systemic antibiotic agents were used was 14.4%, compared to the combination of systemic therapy and locally administered antibiotic agents, of 2.4%. Of the 21 articles reviewed, 15 contained evidence graded as low, 5 were moderate quality, and 1 that was a large multicenter randomized controlled trial and was graded high.⁴⁰

Antibiotic-coated implants are utilized to treat complex open fractures and revisions. One such implant for trauma related fractures is a tibial nail coated with a layer of poly(d,l-Lactide) (PDLLA) impregnated with gentamicin. In 2015, Metsemakers et al.⁴³ performed a single-center retrospective evaluation of the ETN PROtect™ (DepuySynthes, Johnson/Johnson Company, Inc., New Jersey, USA) for the prevention of deep infection in type II–III acute open tibial fractures or closed tibia fractures with initial long-term (>2 weeks) external fixation before intramedullary nailing (IMN) and complex revisions with a mean of 3 prior surgical interventions. Outcome measures were infection, superficial or deep (implant-related), and non-union during the 18-month follow-up period. Patients received systemic prophylactic antibiotic agents pre-operatively and post-operatively for the open fractures until wound closure with a maximum therapy of 5 days. Patients received a cephalosporin and those with a type III open fracture also received an aminoglycoside. Sixteen patients with 16 fractures were included. Group 1 consisted of 11 patients with acute fractures and 9 with open tibial fractures. Of the 9 open fractures, 4 were type II, 2 were type IIIA, and 3 were type IIIB. Group 2 consisted of 5 complex revision cases, and infected non-union was the main reason for using the ETN PROtect™ nail. There were no deep infections after implant use. Four patients had non-union requiring additional surgical procedures, with 1 in the complex revision group.⁴³

Local injection of aminoglycosides has been implemented for prophylaxis against infection in open fractures in conjunction with systemic antibiotic agents. In 2015, Lawing et al.⁴⁴ conducted a retrospective review to determine efficacy of local wound cavity injections with aminoglycosides in addition to systemic antibiotic agents to lower prevalence of infections. Systemic antibiotic agents included cefazolin for type I and II fractures or clindamycin if penicillin-allergic. Patients with type III fractures received weight-based gentamicin and penicillin G for barnyard contamination. Local antibiotic agents consisted of gentamicin until 2011 and tobramycin thereafter. Aminoglycoside (80 mg) diluted in 40 mL of saline was injected into the wound cavity. There were 183 (84 type III) patients in the systemic antibiotic agents alone control group and 168 (84 type III) patients in the combination local and systemic antibiotic group. Rates of deep and superficial infections in the control group were 19.7% (36/183) versus 9.5% in the combination group (p = 0.01). There was a difference in deep infections between control and combination groups (14.2% vs. 6%; p = 0.011). Study limitations include its retrospective nature and decisions by the treating surgeon determined inclusion into the combination therapy group. Of note, one senior author contributed almost half of the patients to this cohort.⁴⁴

In 2017, van Niekerk et al.⁴⁵ published a retrospective cohort study examining cemented polymethylmethacrylate (PMMA) spacer application in combination with circular external fixation in patients with type III open fractures. The authors included 24 of 26 originally identified patients. Patients sustained either acute type III open tibial fractures or infected tibial non-unions, and all underwent surgical treatment according to the institutional standardized protocol. The antibiotic-impregnated PMMA spacer (Palacos^®; Zimmer, Warsaw, IN) was inserted into the bone defect for local antibiotic therapy and to preserve space for definitive bone reconstruction. Patients received 6 weeks of antibiotic therapy according to culture and sensitivity results. Authors measured time in the external fixator (EFT) and the external fixation index (EFI) was calculated by dividing time (days) by the lengthening achieved (centimeters). They observed a longer EFI for patients with an infected non-union than those treated for open fractures with segmental bone loss (56 ± 14.5 cm/days vs. 37.3 ± 9.1 cm/days; p = 0.027). They concluded antibiotic-impregnated spacers for open tibial trauma were advantageous and reduced the EFI considerably.⁴⁵

In Type III open extremity fractures with associated bone loss, we recommend administration of local antibiotic therapy in addition to systemic therapy to decrease infectious complications. Additional data are needed to determine if there are benefits to patients in terms of decreased hospital length of stay or mortality.

Level 2C

Discussion

Here we provide updated recommendations for prophylactic antibiotic use in the setting of open extremity fractures. The original Surgical Infection Society guideline by Hauser et al.⁸ states that short courses of first-generation cephalosporins, initiated as soon as possible after injury, significantly reduce the risk of infection when combined with expeditious orthopedic fracture management. The authors provide sufficient data to support prophylaxis with 24-48 hours of peri-operative antibiotic agents directed against gram-positive bacteria for type I, II, and III open fractures. The authors report insufficient evidence to support prolonged courses of antibiotic agents or administration of extended antimicrobial coverage. Our updated review of the literature is consistent with these findings and demonstrates that in type I, II, or III open extremity fractures, there is no benefit of extended-spectrum antibiotic coverage compared with gram-positive coverage alone to decrease infectious complications, hospital length of stay, or mortality. This review demonstrates that in type III open extremity fractures, there is no benefit to administering antibiotic agents for more than 24 hours after injury to decrease infectious complications, hospital length of stay, or mortality. Although our literature review does not specifically address duration of prophylaxis in type I or II open fractures, we believe it is reasonable to defer back to the 2006 recommendations⁸ for these injuries, especially considering the evidence presented here shows no benefit to prolonged antibiotic courses for more severe injury patterns. Finally, although Hauser et al.⁸ report insufficient evidence to support local therapies including antibiotic beads, more recent evidence shows that in type III open extremity fractures with associated bone loss, administration of local antibiotic therapy in addition to systemic therapy may decrease infectious complications.

Although clinical guidelines for antibiotic prophylaxis in open extremity fractures favor administration of narrow-spectrum antibiotic agents for shorter durations, recent surveys indicate clinical practice patterns differ in approach. In 2019, Puetzler et al.⁴⁶ distributed an anonymous SurveyMonkey questionnaire to 1,197 orthopedic trauma surgeons worldwide regarding prophylaxis against infection during fracture care. For the question of whether gram-negative antibiotic coverage is important to open fracture care, more than 25% of surgeons responded agree or strongly agree for type I injuries and 65% answered similarly for type II fractures. First-choice antibiotic agents for peri-operative prophylaxis in type I or II open fractures often included agents targeting gram-negative organisms. In 2019, Chang et al.⁴⁷ conducted a systematic survey of 100 clinical practice patterns and 276 clinical recommendations regarding systemic antibiotic administration in open fractures published between 2007 and 2017. The most substantial difference was between practice patterns and clinical recommendations for antibiotic prescribing after type I and II open fractures. Very few clinicians restrict coverage to gram-positive organisms for these fracture patterns. Indeed, most providers provide gram-negative coverage with either aminoglycosides or broad-spectrum agents including carbapenems, third- or fourth-generation cephalosporins, or piperacillin-tazobactam.

This discrepancy between practice patterns and published guidelines may relate to concerns regarding infection risk from modern bacterial flora. In 2020, Sudduth et al.⁴⁸ published a retrospective review of 451 patients with open long-bone fractures treated at a level 1 trauma center between 2008 and 2012.⁴⁸ All patients received cefazolin and gentamicin on admission regardless of fracture grade. The authors reported infections in 20% of patients, with the rate of infection increasing from 5% in type I to 13% in type II open fractures. For type I and II injuries, MRSA was present in 21% of cultures, gram-negative organisms in 64% of cases, and 50% of infections were polymicrobial. Among 5% of tested gram-positive infections, only 50% of organisms were sensitive to cefazolin, the most commonly prescribed cephalosporin. Sensitivity to oxacillin was less than 40%. Overall gram-positive sensitivity was 59%. The authors concluded that current antibiotic regimens for open fractures may require reconsideration. Lastly, Obremskey et al.⁴⁹ surveyed 379 members (25% response rate) of the Orthopedic Trauma Association between July and August of 2012. They found that only 39% of respondents reported stopping antibiotic coverage at 48 hours in type IIIA and IIIB fractures.⁴⁹

Future Directions

Although antibiotic agents remain a standard of care for infection prevention after open extremity fractures, our findings and surveys of clinical practice patterns clearly show that additional robust clinical trials are needed to provide stronger corroborating evidence. Current recommendations are based on relatively few studies of lower quality. Multiple unresolved issues remain regarding optimal systemic or local antibiotic regimens for different fracture types. Evolving bacterial flora and antimicrobial resistance patterns require further study. There may be important geographic differences as well. Last, considering the literature in this field has changed very little over nearly 50 years, any future novel findings or therapeutic advances will require substantial outreach efforts to enact substantive changes in patient care.

Footnotes

Funding Information

There is no funding associated with this manuscript.

Author Disclosure Statement

No conflicts of interest are reported for any author.

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