Infection prevention for open fractures: Is antibiotic monotherapy equivalent to multitherapy?

Open extremity fractures (OEFx) continue to exact a disproportionately heavy toll on trauma victims across the world. Among the populations most susceptible to the most severe sequelae of OEFx – such as severe infection, compartment syndrome, disability, amputation, and mortality – are patients from vulnerable populations, limited-resource environments, and disaster-stricken regions.[12345678] Given the critical nature of early recognition, timely and appropriate antimicrobial therapy, and prompt surgical treatment of OEFx, various national and international organizations advocate for protocolized, multidisciplinary, evidence-based approaches aimed at improving clinical outcomes for the affected patients.[3591011] Within this broader context, the research continues into the most optimal approaches toward antibiotic prophylaxis for patients with OEFx[1213]– the focus of both our Editorial and the Original Article by Depcinski et al.[12] in the current issue of the International Journal of Critical Illness and Injury Science (IJCIIS).

The Gustilo and Anderson classification is the most widely used classification for OEFx.[14] They categorized open injuries into three categories: based on wound size, contamination level, and osseous damage as follows: (i) wound ≤1 cm, minimal contamination or muscle damage; (ii) wound 1–10 cm, moderate soft-tissue injury (without extensive soft-tissue damage, flaps, or avulsions); (iiia) wound usually >10 cm, high energy, extensive soft-tissue damage, contaminated, adequate tissue for flap coverage, and farm injuries; (iiib) extensive periosteal stripping, wound requires soft-tissue coverage (rotational or free flap); and (iiic) vascular injury requiring vascular repair, regardless of degree of soft-tissue injury. The incidence of wound infection correlates directly with the grade of fracture: type I (0%–2%); Type II (2%–7%); Type IIIA (7%); Type IIIB (10%–50%); and Type IIIC (25%–50%).[15] Infection rates for OEFx involving the hand and upper extremity are lower compared with those of the lower extremity.[16]

The theoretical basis for the effective antibiotic prophylactic in the setting of OEFx was established in the late 1950s.[1718] The use of antibiotics has been a standard management tool to either prevent or treat infection of OEFx; however, based on the existing practice guidelines and clinical trials, the optimal antibiotic prophylaxis for Type III open fractures remains uncertain. Experts propose preoperative prophylactic antibiotics for OEFx to be started “as soon as possible after injury.[1920] Initiating antibiotic prophylaxis within 1 h[19] or even 3 h[21] of injury has been shown to reduce infection rates. Furthermore, the participation of a pharmacist during the initial trauma resuscitation may further improve door-to-antibiotic administration times.[20]

Regarding the duration of therapy, the guidelines make a Level III recommendation for antibiotics to be discontinued 24 h after wound closure for Grade I and II fractures. For Grade III fractures, the guidelines recommend antibiotics to be continued for the earliest of either 72 h after the time of injury or 24 h after soft-tissue coverage of the wound. This is based on the evidence showing that shorter antibiotic regimens (<72 h) were equivalent to longer regimens (<72 h) in preventing infection.[222324]

Although narrow-spectrum antimicrobial prophylaxis is recommended by the evidence-based guidelines, many trauma centers use broad-spectrum antibiotics. There is substantial morbidity related to the use of broad-spectrum antibiotics in the OEFx population, including potential acute kidney injury with the use of aminoglycosides, development of antimicrobial resistance, and superinfections with multidrug-resistant organisms.[252627]

In this issue of IJCIIS, Depcinski et al.[12] set out to compare the merits of single-agent cefazolin versus cefazolin + gentamycin. Although there are intrinsic limitations to the retrospective approach, and the study was not adequately powered to assess for noninferiority, there are important insights to be gained from their efforts. This has been a controversial topic in recent years. In another study using a retrospective cohort design (n = 167), the authors reported no difference in infection rates between those patients treated with or without the addition of a systemic aminoglycoside.[28] Moreover, in a before and after study (n = 174) where aminoglycosides were removed from the treatment protocol, no difference was observed in per fracture event rate of resistant Gram-positive or Gram-negative organisms or in methicillin-resistant Staphylococcus aureus.[26]

Important to note, however, is that many of the studies did not distinguish between deep and superficial infections. Those that have focused on deep infections have often looked at the addition of locally administered (rather than systemic) aminoglycosides. Several studies have reported lower deep infection rates with locally administered aminoglycosides.[29] Meanwhile, critics of the adding aminoglycosides have argued that a small benefit with expanded Gram-negative coverage may not extend to a decreased risk of osteomyelitis, rates of hardware removal,[30] nonunion rates,[29] and may not outweigh the additional costs in terms of increased antibiotic resistance and adverse effects.[31] Changes in rates of acute kidney injury with addition of an aminoglycoside are controversial, and studies have been conflicting in the findings.[2830]

Despite growing evidence that antibiotic monotherapy may be similarly efficacious as multitherapy for preventing infectious complications of OEFx, the data are incomplete. This movement has been largely based on underpowered retrospective studies utilizing varied endpoints. We encourage investigators to move forward to a randomized controlled study design to more definitively clarify this issue.