Antibiotic Prophylaxis in Open Fractures

Evidence, Evolving Issues, and Recommendations

Matthew R. Garner, MD; Saranya A. Sethuraman, MD; Meredith A. Schade, MD; Henry Boateng, MD

Disclosures

J Am Acad Orthop Surg. 2020;28(8):309-315. 

In This Article

Classes of Prophylactic Antibiotics

Beta-lactam Antibiotics

Penicillins and cephalosporins are beta-lactam antibiotics that work in a bactericidal fashion. They attach to penicillin-binding proteins and prevent cell wall synthesis, leading to cell lysis and death. Microbes can be resistant to beta-lactams, but penicillin continues to be the preferred antibiotic against Clostridium species associated with barnyard injuries contaminated with soil or feces.[6] In a study of wound cultures from 352 consecutive open long bone fractures done in 1976, 60% grew gram-positive cocci susceptible to cephalothin.[1] Since then, first-generation cephalosporins have been the most common and most effective prophylactic agent given after open fractures. The infection rate after cefazolin prophylaxis is markedly lower when compared with the use of penicillin or streptomycin.[7] The early administration of first-generation cephalosporins in patients with open fractures is broadly supported as is evident in systematic reviews by both Isaac et al and Chang et al.[8,9] Because gram-positive cocci are the most common infectious agent in open fractures, the Surgical Infection Society, a consortium of surgeons and infectious disease specialists, suggests coverage with clindamycin in penicillin-allergic patients,[10] and the Eastern Association for the Surgery of Trauma updated its recommendations in 2011 to suggest usage of vancomycin in penicillin-allergic patients presenting to hospitals with a high rate of community-acquired methicillin-resistant Staphylococcus aureus (MRSA) infections.[6]

Piperacillin-Tazobactam. It is a bactericidal combination of a β-lactam and a beta-lactamase inhibitor that provides broad-spectrum gram-positive, gram-negative, and anaerobic coverage. Data on use in the setting of open fractures are limited, but Redfern et al[11] have demonstrated noninferiority in type III open injuries as monotherapy when compared with dual therapy with cefazolin and gentamicin. Use of piperacillin-tazobactam in this setting may serve to limit variability and confusion with regard to dosing, as well as limit potential adverse reactions to aminoglycosides in the setting of severe open injuries.

Monobactams. Aztreonam is a bactericidal antibiotic that also interferes with cell wall synthesis. It has activity against aerobic gram-negative organisms including Pseudomonas aeruginosa, but has no gram-positive or anaerobic coverage. It can be inactivated by extended-spectrum beta-lactamases. Aztreonam is not nephrotoxic but is renally excreted, and dose adjustment is required for patients with renal dysfunction.[12] Aztreonam can be used in place of an aminoglycoside, especially in patients at risk of kidney injury. It also may be used in penicillin-allergic patients with type III fractures in conjunction with gram-positive coverage.[13]

Lincosamides

They represent a small class of antibiotics that function to inhibit protein synthesis by binding to the 50S subunit of bacterial ribosomes. Within this class, clindamycin provides gram-positive coverage and is therefore commonly used and recommended in patients with open fractures who have an allergy to penicillin. Isolated data regarding the nuse of clindamycin in open fractures are limited because patients who are treated with clindamycin are generally pooled with those treated with cefazolin. Patzakis et al conducted a randomized controlled trial looking at clindamycin as a single agent in the prevention of infection in open fractures. Infection rates were comparable with the use of dual-agent therapy (cefamandole/gentamicin) for type I and type II open fractures.[14]

Aminoglycosides

These are concentration-dependent bactericidal antibiotics that work by inhibiting the 30S subunit of the bacterial ribosome. They act against most aerobic gram-negative organisms and were historically widely used for prophylaxis after open fractures[15] but have fallen out of favor because of dose-dependent reversible nephrotoxicity and irreversible ototoxicity. Gram-negative organisms are more likely to be the source of surgical site infections in type III open fractures, which therefore warrant broader coverage than a first-generation cephalosporin.[6] Therefore, aminoglycosides are commonly used in more severe open injuries as a way to prevent gram-negative infections.

Bankhead-Kendall et al[16] reported a series of 126 type III fractures treated at their institution over a five-year period. Antibiotic prophylaxis was based on the treating surgeons' preferences, and roughly half of patients (52%) were treated with a first-generation cephalosporin, while the other half (48%) were treated with the addition of an aminoglycoside. No difference in surgical site infection was seen, but a statistically notable increase in acute kidney injury was noted in those treated with aminoglycosides. Tessier et al[17] demonstrated no increased risk of acute kidney injury with prophylactic gentamicin administered at presentation, with an odds ratio of 0.22 (95% CI 0.02 to 2.44). However, they also demonstrated and increasing risk of acute kidney injury with higher injury severity scores and hypotension on presentation.[17] Redfern et al[11] demonstrated no statistical difference in infection rates at 30 days or 1 year after open injury when patients were given cefazolin and gentamicin or only piperacillin-tazobactam (32.4% versus 31.4%, P = 1).

Adverse effects attributed to use of aminoglycosides are exposure-dependent, and therefore, once-daily dosing of gentamicin, generally 5 mg/kg/d, is preferred if aminoglycosides are to be used.[18] In a study of 219 patients with type II or III open fractures, daily gentamicin dosing had a lower rate of infection when compared with divided dosing with the equivalent of 5 mg/kg/d given over three doses (6.7% versus 13.6), although this difference did not achieve statistical significance.[19] At the present time, there is insufficient evidence to support routine gram-negative coverage in prophylaxis for all open fractures.[10] Furthermore, given concerns for nephrotoxicity and a lack of evidence supporting its clinical efficacy, we recommend against the use of aminoglycosides in the prophylactic management of open fractures.

Fluoroquinolones

Fluoroquinolones exert a bactericidal effect by inhibiting DNA gyrase and topoisomerases and preventing bacterial DNA replication. They cover gram-positive microbes and a similar range of gram-negative organisms as aminoglycosides but confer a lower risk of nephrotoxicity and ototoxicity. Deep surgical site infection rates after type IIIA open fractures were 5.4% when covering with cefazolin and gentamicin and 6.5% when covering with cefazolin and ciprofloxacin in a series of 215 patients.[20] Elderly patients and those with independent risk factors for kidney injury due to trauma may benefit from combination prophylaxis with a first-generation cephalosporin and a fluoroquinolone rather than an aminoglycoside antibiotic.[17] Fluoroquinolone-only coverage had a 31% rate of infection in a combined analysis of all type III open fractures compared with 7.7% for a cephalosporin and aminoglycoside combination in a series of 171 open fractures; the infection rates were similar (5.8% and 6.0%, respectively) in type I and II open fractures.[14]

Although exact mechanisms are not clearly defined, some fluoroquinolones inhibit the hepatic metabolism of warfarin, heightening bleeding risk in elderly patients already on therapeutic anticoagulation.[21] Extreme caution should be used in the patient cohort, and fluoroquinolones should be avoided if possible. Fluoroquinolones also have a dose-dependent cytotoxic effect on bone healing in in vivo studies in rats.[22] Ciprofloxacin-treated rat femur fractures showed less bridging bone and diminished torsional strength than those treated with cefazolin 4 weeks after fracture. Cefazolin-treated fractures were not markedly different from the control in torsional strength or stiffness.[22] Histologically, ciprofloxacin treatment showed callus formation incompletely filled with hypocellular cartilage, indicating inhibition of endochondral ossification. Therefore, the use of fluoroquinolones is contraindicated in the pediatric open fracture patient, but effects on adults are less well-delineated.

Glycopeptides

Vancomycin, a glycosylated peptide produced by a soil bacterium, is an alternative choice for coverage against gram-positive organisms in penicillin-allergic patients.[6] Vancomycin inhibits bacterial synthesis by blocking peptidoglycan polymerization. It has time-dependent killing and is slowly bactericidal. Official guidelines state there is insufficient evidence for use of vancomycin alone as open fracture prophylaxis.[10] Vancomycin is now most often used to treat MRSA infections; however, MRSA carriers are more likely to develop MRSA surgical site infections regardless of prophylactic coverage with vancomycin, at a rate of 33% versus 1% in patients negative for MRSA colonization on routine admission surveillance (P = 0.003).[23] A review of 1,539 patients showed that the combination of vancomycin and cefepime reduced infection rates in type III open fractures by 3.7% (P = 0.03) compared with the combination of cefazolin and gentamicin.[24] In the same study, the rate of vancomycin-resistant MRSA was not markedly increased.

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