Introduction

1. Open fracture wounds are considered high energy injuries that come with a high risk of infection due to the potential exposure of bone and tissue to environmental pathogens.
2. The Gustilo- Anderson classification system grades open fractures and can be utilized to guide antimicrobial prophylaxis.
3. For Type I fractures, which are clean wounds less than 1 centimeter long, gram positive coverage is recommended; cefazolin is usually the agent of choice.
4. For Type II factures, which are wounds greater than 1 centimeter long without extensive soft tissue damage, gram positive coverage is recommended; cefazolin is usually the agent of choice.
5. For Type III fractures, which are open segmental fractures that have extensive soft tissue damage, gram negative coverage is recommended, in addition to gram positive coverage. Aminoglycosides such as gentamicin formerly were the gram-negative agent of choice, to be given in addition to an agent such as cefazolin. However, more recently monotherapies such as ceftriaxone and piperacillin-tazobactam have been studied as a potential alternative. Type III fractures may carry an infection risk up to 50%.
6. For injuries involving fecal or clostridial contamination such as farm-related injuries, high dose penicillin should be added as well. For injuries with saltwater contamination, the addition of doxycycline should also be considered.

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Pharmacology
	Ceftriaxone	Cefazolin	Gentamicin
Dose	2 grams	2 grams (3 grams if >120 kg)	5 mg/kg
Administration	IV as a bolus over 3 to 5 minutes	IV as a bolus over 3 to 5 minutes	IV infusion over 30 to 120 minutes
PK/PD	Vd: ~6 to 14 L T1/2: ~5 to 9 hours	Vd: 0.193 ± 0.064 L/kg T1/2: 1.8 hours Time to peak: within 5 mins	Vd: 0.2 to 0.3 L/kg T1/2: 2 hours Time to peak: 30 minutes after 30 min infusion
Adverse Effects	Skin rash; GI ADEs	Skin rash; GI ADEs	Nephrotoxicity; neurotoxicity (including ototoxicity)
Drug Interactions and warnings	Drug interactions: aminoglycosides, warfarin, probenecidWarnings: may elevate INR	Drug interactions: aminoglycosides, warfarin, fosphenytoin, rifampin, probenecidWarnings: may elevate INR; cause in caution with penicillin allergy	Drug interactions: other nephrotoxic agents; neuromuscular blockersWarnings: may cause irreversible renal damage; may cause neuromuscular blockade and respiratory paralysis; may cause irreversible neurotoxicity
Compatibility	Compatible with NS, D5W Not compatible with LR	Compatible with LR, NS, D5W	Compatible with LR, NS

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	Overview of Evidence
Author, year	Design/ sample size	Intervention & Comparison	Outcome
O’Connell, 2022	Single-center retrospective cohort study (n=120) in type III open fractures	Piperacillin-tazobactam (PT) vs cefazolin with or without aminoglycoside	Per univariate analysis, more infections in PT group (23.7% vs. 4.3%; p = 0.042), however per multivariate analysis, antibiotic choice was not a predictor of infection (OR, 5.81 [95% CI, 0.73–46.25; p = 0.096])
Shawar, 2020	Single-center retrospective cohort study (n=82) in type III open fractures	High dose tobramycin with either cefazolin or clindamycin vs PT	Faster time to admin: 179 mins vs 77 mins (p<0.05) with PT   Fewer surgical site infections (SSI) at 30 days: 27.5% vs 4.3% (p = 0.033) and at 60 days: 32% vs 4.3% (p = 0.009) with PT
Depcinski, 2019	Single-center retrospective cohort study (n=68) in type III open fractures	Cefazolin alone vs cefazolin with an aminoglycoside	Greater rates of infection in combination group: (40% vs 15.1%, P = 0.035)
Patanwala, 2019	Single-center retrospective cohort study (n=134) in type III open fractures	Cefazolin alone vs cefazolin with an aminoglycoside	No difference in rate of infection: (15% vs 16%, P = 1.000)
Redfern, 2016	Single-center retrospective study (n=72) in type III open fractures	Cefazolin with gentamicin vs PT	No difference in rate of SSI at 30 days (21.69% vs 11.4%; p = 0.246) or 1 year (32.4% vs 31.4%; p = 1.000)
Rodriguez, 2014	Single-center retrospective study (n=174) in open fractures	Pre-protocol (grade I-II cefazolin, grade III cefazolin plus gentamicin) vs post-protocol (cefazolin for grade I-II, ceftriaxone for grade III)	No difference in rate of SSI (20.8% vs 24.7%; p = 0.58)
Patzakis, 1974	Single center retrospective study (n=310) in open fractures	Penicillin plus streptomycin vs cephalothin vs no antibiotics	Rate of infection: 9.7% v 2.3% vs 13.9%
Gustilo, 1976	Retrospective (n= 673) and prospective (n=352) analysis in open fractures	In retrospective study, from 1955-1960, patients given penicillin and streptomycin; from 1961- 1967, patients given penicillin and chloramphenicol   In prospective study, patients given oxacillin-ampicillin before surgery	Retrospective infection rate: from 1955-1960, 12% vs from 1961-1968, 5% Prospective infection rate: 2.5% For type III open fractures specifically, infection rates 44% in retrospective study; 9% in prospective study

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Conclusions

Antimicrobial prophylaxis is an important component of open fracture management; without appropriate antibiotic selection, infection rates may be up to 50%. For grade I and II fractures, gram positive coverage is needed, and cefazolin is a reasonable agent of choice. For grade III fractures, broadened coverage included gram negatives is recommended. Emerging evidence suggest ceftriaxone or piperacillin-tazobactam may be reasonable agents of choice.

References

1. Ceftriaxone. Micromedex [Electronic version].Greenwood Village, CO: Truven Health Analytics. Retrieved February 10, 2022, from http://www.micromedexsolutions.com/
2. Cefazolin. Micromedex [Electronic version].Greenwood Village, CO: Truven Health Analytics. Retrieved February 10, 2022, from http://www.micromedexsolutions.com/
3. Gentacicin (systemic). Micromedex [Electronic version].Greenwood Village, CO: Truven Health Analytics. Retrieved February 10, 2022, from http://www.micromedexsolutions.com/
4. O’Connell CR, Kooda KJ, Sawyer MD, Wise KB, Mara KC, Skrupky LP. Evaluation of Piperacillin-Tazobactam for Antibiotic Prophylaxis in Traumatic Grade III Open Fractures. Surg Infect (Larchmt). 2022 Feb;23(1):41-46. doi: 10.1089/sur.2021.122. Epub 2021 Oct 5. PMID: 34612703.
5. Shawar SK, Ly TV, Li J, Shirk MB, Reichert EM. Piperacillin/Tazobactam versus Tobramycin-Based Antibiotic Prophylaxis for Type III Open Fractures. Surg Infect (Larchmt). 2020 Feb;21(1):23-28. doi: 10.1089/sur.2019.064. Epub 2019 Aug 5. PMID: 31381489.
6. Depcinski SC, Nguyen KH, Ender PT. Cefazolin and an aminoglycoside compared with cefazolin alone for the antimicrobial prophylaxis of type III open orthopedic fractures. Int J Crit Illn Inj Sci. 2019 Jul-Sep;9(3):127-131. doi: 10.4103/IJCIIS.IJCIIS_7_19. Epub 2019 Sep 30. PMID: 31620351; PMCID: PMC6792399.
7. Patanwala AE, Radosevich JJ, Meshay I, Naderi M, Culver MA, Lee YG, Weinberg JA, Khobrani M, Nix DE. Cefazolin Monotherapy Versus Cefazolin Plus Aminoglycosides for Antimicrobial Prophylaxis of Type III Open Fractures. Am J Ther. 2019 Nov 25;28(3):e284-e291. doi: 10.1097/MJT.0000000000001121. PMID: 31789627.
8. Redfern J, Wasilko SM, Groth ME, McMillian WD, Bartlett CS 3rd. Surgical Site Infections in Patients With Type 3 Open Fractures: Comparing Antibiotic Prophylaxis With Cefazolin Plus Gentamicin Versus Piperacillin/Tazobactam. J Orthop Trauma. 2016 Aug;30(8):415-9.
9. Rodriguez L, Jung HS, Goulet JA, Cicalo A, Machado-Aranda DA, Napolitano LM. Evidence-based protocol for prophylactic antibiotics in open fractures: improved antibiotic stewardship with no increase in infection rates. J Trauma Acute Care Surg. 2014 Sep;77(3):400-7; discussion 407-8; quiz 524.
10. Patzakis MJ, Harvey JP Jr, Ivler D. The role of antibiotics in the management of open fractures. J Bone Joint Surg Am. 1974 Apr;56(3):532-41.
11. 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 Jun;58(4):453-8.