Authors: Kitana Caesar, PharmD Candidate 2022 and Gabrielle Gibson, PharmD, BCPS, BCCCP
Open fractures are injuries frequently seen in emergency departments or trauma centers. Typically, the skin barrier has been compromised, exposing the sterile bone to environmental debris and soft tissue damage. Exposure to the ambient environment places these wounds at an increased risk of infection.1 The Gustilo-Anderson classification system is utilized to grade the severity of open fractures, and to determine appropriate antibiotic prophylaxis (Table 1). The infection rates for grade I/II fractures range from 0 to 7% whereas the grade III fracture infection rate ranges from 5 to 50% without antibiotic prophylaxis.3 Ineffective prophylaxis may lead to complications such as nonunion of bones and osteomyelitis.2 In fact, 19% of osteomyelitis cases are secondary to traumatic injury. As such, the use of antibiotic prophylaxis to decrease the rate of infective complications after open fractures has been considered standard of care for over 30 years.
As with many historic practices, the justifications for the use of antibiotics have become obscured over time. Recent studies have been based on the standards established by a few key papers with no re-evaluation of the application of those principles in the setting of modern open fracture management nor today’s antibiotic and bacterial resistance patterns. As a result, open fracture antibiotic prophylaxis is currently defined and instituted variably, and evaluation of recommended approaches has been slowed by reluctance to challenge familiar practice patterns. Further complicating standardization is the lack of recommendations for a specific antibiotic and dose combination in open fracture guidelines.1,4 Therefore, this review will aim to analyze antibiotic prophylaxis regimens as well as suggested durations of therapy.
The most common pathogens involved in grade I/II fractures include Gram-positive bacteria (e.g.: Streptococcus spp. and Staphylococcus spp.).1 Patients presenting with grade III fractures and exposure to certain environmental factors are predisposed to infections involving Gram-negative bacteria (e.g.: Enterobacter cloacae and Pseudomonas aeruginosa).1 Increased presence of methicillin resistant Staphylococcus aureus (MRSA) occurs in patients with prior MRSA infection, prior MRSA nasal carriage, wounds present on admission, nursing home residents, recent prolonged health system exposure, and comorbidities, including diabetes or heart failure.5 Prophylactic antibiotic regimens should therefore be tailored to the severity of the fracture and the environment in which the fracture took place. The Eastern Association for the Surgery of Trauma (EAST) guidelines recommend that antibiotic coverage be directed at Gram-positive organisms and additional Gram-negative coverage be added for grade III fractures.1 The Surgical Infection Society (SIS) guidelines recommend first-generation cephalosporins be initiated as soon as possible but make no recommendations for gram-negative or clostridial coverage (Table 2).4
The aforementioned antibiotic recommendations largely originated from a study by Patzakis and colleagues published in 1974.6 This randomized, placebo-controlled trial was the first to examine infection rates in open fractures in relation to antibiotic use and as such, it continues to impact practice today. This study included 310 patients with open fractures (not graded for severity) over a one year period. Patients were randomized to three groups: no antibiotics, penicillin and streptomycin (aminoglycoside), or cephalothin (first-generation cephalosporin with a spectrum of activity similar to cefazolin) for 10–14 days. The study found that patients receiving cephalothin had a lower incidence of infection (2.4%) than the penicillin/streptomycin group (9.8%) and the control group (13.9%), with statistical significance between placebo and cephalothin groups only.6 These data provided strong evidence for the efficacy of first-generation cephalosporins in managing open fractures. In the same study, the investigators described the bacteria that caused the fractures to become infected. In the placebo group, the isolated organisms included Gram-positive, Gram-negative, and rarely Clostridium spp. The penicillin/streptomycin group developed infections with Staphylococcus aureus and Enterobacterales including Pseudomonas spp., whereas the cephalothin group demonstrated infections with gram-negative species.6 These findings led the authors to suggest that combination streptomycin and a cephalosporin would reduce infection rates further. However, this hypothesis was never tested and remains an extrapolation unsupported by the data. Nonetheless, conclusions from this study have been cited for over 30 years.
Therefore, the current recommended antibiotic for all fracture grades is a cephalosporin (including first-, second-, and third-generation). Expanded Gram-negative coverage is recommended for grade III fractures if a first- or second-generation cephalosporin is selected, and additional anaerobic coverage is needed if the fracture is contaminated with soil or fecal matter. Guidelines do not recommend a specific Gram-negative agent, but aminoglycosides are widely used for prophylaxis in open fractures. Recently, the use of aminoglycosides has fallen out of favor due to nephrotoxicity and ototoxicity. A study by Bankhead-Kendall and colleagues evaluated 126 grade III fractures at their institution over a 5-year period.7 Antibiotic prophylaxis was based on the treating surgeon’s preferences, and roughly half (52%) were treated with a first-generation cephalosporin, while the other half (48%) were treated with the addition of an aminoglycoside. No difference was observed in surgical site infection, but there was a statistically significant increase in acute kidney injury in those treated with an aminoglycoside.7 Currently, there is insufficient evidence to support routine gram-negative coverage in prophylaxis for all open fractures.4 Additionally, in the event of a true allergy to cephalosporins, clindamycin and aztreonam may be considered for gram-positive and gram-negative coverage.1 Vancomycin is reasonable to add if patients have risk factors for a MRSA infection (Table 2).
A study by Rodriguez and colleagues evaluated a new protocol that was implemented at their institution. This pre- and post-protocol implementation analyzed 174 patients (101 pre-protocol and 73 post-protocol) with open fracture and stratified groups according to Gustilo-Anderson fracture grade, fracture site, and persistence of resistant organisms. Patients with grade I/II fractures received cefazolin while patients with grade III fractures received ceftriaxone for 48 hours. Aminoglycosides, penicillin, and vancomycin were removed from the post-protocol. There was no difference in skin or soft tissue infection rate per fracture before or after protocol implementation (20.8% vs 24.7%, p=0.58). The authors concluded that implementation of an evidence-based, narrow spectrum antimicrobial prophylaxis protocol resulted in similar infection rates.3 This was one of the first trials to challenge the use of broad-spectrum antibiotics and aminoglycosides when potentially less toxic and narrower agents could be considered.
The duration of antibiotic prophylaxis is a crucial aspect in the management of open fractures. The SIS and EAST guidelines recommend starting antibiotics immediately following injury in all fracture types.1,4 Antibiotics are continued for 24-72 hours depending on the severity of the open fracture and the time soft tissue coverage occurs. For grade III fractures, the EAST guidelines suggest continuing antibiotics for 72 hours after injury but not greater than 24 hours from the time soft tissue coverage is achieved.1 Chang et al demonstrated through a meta-analysis that infection rates between longer durations (3-5 days) and shorter duration (1 day) of antibiotics were no different. However, there was significant risk of bias present considering the included publications were largely provider-reported reviews of practice recommendations whose focus was not antibiotics.8 The SIS guidelines suggest that 48 hours of therapy may be appropriate in grade II fractures, but longer courses of antibiotics do not reduce the risk of infection and can lead to the development of drug resistant organisms and increased adverse effects.4,9 Accordingly, a duration of 24 hours for all fracture types is considered adequate prophylaxis, with special consideration for longer durations (up to 72 hours) in higher grade fractures.
Open fractures of all grades have a risk of infection, and patients benefit from antibiotic prophylaxis. Differences in the recommended antibiotic regimen and durations persist and understandably, optimal prophylactic antibiotic therapy may be dependent on the context of the injury. Although there are limited data supporting the efficacy of narrow-spectrum antibiotics for shorter durations of therapy, developing a unified approach regarding optimal therapy and duration for open fracture antibiotic prophylaxis will require a large, randomized trial.