DRAFT

Level 1

There is sufficient Class I and II data to recommend preoperative dosing of prophylactic antibiotics for coverage of gram positive organisms in trauma patients with open fractures as a standard of care. For Grade III fractures, additional coverage for gram negative organisms should be given. High dose penicillin should be added to the antibiotic regimen for barnyard wounds.

Level 2

There is sufficient Class I and Class II data to recommend that antibiotics be discontinued after 24 hours for Grade I and II fractures. For Grade III wounds, the antibiotics should be continued for 72 hours after the time of injury or until soft tissue coverage of the wound is achieved, whichever occurs first.

Extremity fractures are caused by either low or high energy forces, and may be isolated or combined with other injuries. When the underlying fracture is associated with a cutaneous wound, prevention of wound sepsis remains the primary objective in the management of the soft tissue. There is universal agreement that these wounds require emergency treatment as soon as possible to minimize infectious complications. To help standardize care and comparison of similar injuries in studies, Gustilo et al.¹ classified open fractures into three categories:

Grade (Type) I - Open fracture with a skin wound less than 1 centimeter long and clean.

Grade (Type) II - Open fracture with a laceration more than 1 centimeter long without extensive soft tissue damage, flaps or avulsions.

Grade (Type) III - Either an open segmental fracture, an open fracture with extensive soft tissue damage or a traumatic amputation.

In their review, the infection rate for type III open fractures, was a major problem with an incidence of 24%. Grade III injuries were further stratified in order of worsening prognosis with a wound sepsis rate as follows: IIIa - 4%, IIIb - 52%, IIIc - 42%.²

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.

IIIb - Extensive soft tissue injury loss with periosteal stripping and bone exposure. This is usually associated with massive contamination.

IIIc - Open fractures associated with arterial injury requiring repair.

The standard of care for all open extremity fractures is as follows: The wound is covered with a sterile dressing with gentle pressure applied as necessary to control bleeding and the limb is splinted in the emergency department. Tetanus prophylaxis and parenteral antibiotics are administered. Operative wound care under general or regional anesthesia should occur within 6 hours of injury whenever possible since longer delays increase the risk of infection. This should involve a thorough debridement of devascularized muscle, fascia, subcutaneous tissue, skin, bone and all foreign material. Determination of the grade of the fracture should be made at the time of initial wound excision. The wound is then irrigated with a pulsatile lavage apparatus prior to appropriate stabilization of the fracture. After stabilization, the open traumatic wound is extended as required for debridement and is left open initially under a sterile moisture-retaining dressing. Severe open wounds should be re-examined in the operating room within 24 to 48 hours to assess the adequacy of debridement. The risk of wound infection is reduced when delayed primary closure is accomplished after 3 or 4 days. Wound closure may be accomplished by delayed primary closure, split thickness skin graft, local muscle flap rotation or free tissue transfer with microvascular anastomosis.

Various factors have been recognized as increasing the risk for infection. These include: 1) failure to utilize prophylactic (perioperative) antibiotics; 2) resistance of wound organisms to wound antibiotics; 3) increased time from injury to initiation of antimicrobial agent; 4) extent of soft tissue damage; 5) open tibial fractures; 6) positive post debridement-irrigation cultures; and 7) wound closure in the presence of Clostridium perfringens. Other factors shown to have no effect include the length of antibiotic treatment (3 versus 5 to 10 days) and type of wound closure. Stabilization is now usually obtained by unreamed nailing or external fixation.³ Low infection rates have been reported after severe open fractures treated by reamed intramedullar nailing.⁴ Dellinger et al. performed a multivariant logistic regression analysis and identified local factors at the fracture sight as more significant than ISS, the requirement for blood transfusion, the amount of blood transfused or the presence of more than one fracture as risk factors for subsequent infection.⁵

Norden and colleagues found convincing evidence that antibiotics administered before incision reduced the risk of infection after surgical stabilization of closed hip fractures or replacement with a prosthesis.⁶ The group receiving antibiotics had a 78% lower rate of infection compared to controls. This study is included in this review to demonstrate the role of prophylactic antibiotics following orthopedic procedures for closed fractures. However, they did not address the role of prophylactic antibiotics with regard to open fractures in which bacterial contamination is present preoperatively in 48 to 60% of the wounds.

Dellinger et al. provided a detailed report of prophylactic antibiotics in open fractures in 1991.⁷ This review has a complete detailed analysis of controlled trials in open fractures and the various studies evaluating choices of antibiotics as well as duration of therapy for these extremity injuries. The investigations since then still analyze the impact of various antibiotic regimens and the appropriate length of time for continuing therapy.

1. Identification of references

The recommended guidelines for prophylactic antibiotic usage for open fractures are evidence based. Articles were identified from the literature by independent searches performed by two of the reviewers. One search was performed by using OVID MEDLINE covering the literature from 1985 to the present. Key words utilized in this search were open fracture, antibiotics, prophylaxis and management. References from 1975 to 1985 were identified through a MEDLINE search using the following key words; antibiotic prophylaxis, human, open fractures, bacterial infections - prevention and control, fracture healing, fracture-complications, and surgical wound infections. These combined searches identified 313 articles. The bibliography of each article was reviewed for additional references which were not identified in the two original searches. Letters to the editors, case reports and review articles were deleted from further evaluation. This identified 56 studies for this evidentiary review. The articles were reviewed by 3 orthopedic trauma surgeons, 2 general surgeons and 2 pharmacologists with interest in pharmacokinetics and health care economics. These individuals then collaborated to produce the guidelines.

2. Quality of the references

The references were classified in the methodology established by the Agency for Health Care Policy and Research (AHCPR) of the U.S. Department of Health and Human Services. Additional criteria and use for Class I articles were taken from a tool described by Oxman et al.⁸ Thus, the classifications were I, II, and III:

Class I: Prospective Randomized Double-Blinded Study

Class II: Prospective Randomized Non-Blinded Trial

Class III: Retrospective Analysis of Patient Series

A. Historical background.

An open fracture was for many thousands of years a sentence of death. Amputation was often considerd as the only viable alternative to death. The mortality rate of all kinds of open fracture in the Franco Prussian War was 41%, for the lower leg 50%, for the thigh 66%, and for open fractures of the knee joint 77%. Other reports claimed a mortality rate ranging from 54 to 99% for open femur fractures.⁹

In War World I the mortality rate for an open fractured femur remained approximately 80%. The immediate use of the Thomas splint for femur fractures was introduced in 1916 and the mortality rate for open fractures of the femur promptly fell to 16%. Karpmen later recognized that restoration of the bone length reduced the volume of the fascial compartments and therefore the magnitude of blood loss associated with the open fracture which explained the reduction in mortality observed with the Thomas splint.

In World War I, Orr evolved a policy of wound excision and debridement, reduction of the fracture, stabilization with plaster and leaving the traumatic wound open.¹⁰ During the Spanish Civil War, Truetta confirmed Orr’s experience with a reported 0.6% septic mortality rate in 1069 open fractures.¹¹ Thus, World War I was the first time that the role of wound debridement was correlated with reduction in septic mortality for open fractures. This occurred prior to antibiotics, blood transfusions, intravenous fluids and modern anesthesia.

During World War II there was initial enthusiasm for the use of chemotherapeutic agents primarily in the form of Sulfonamides in the immediate care of open fractures. The importance of wound excision with debridement and healing by secondary intention was once again appreciated when antibiotics failed to reduce infectious complications when wounds were primarily closed. The role of delayed primary wound closure was evaluated in 25,000 wounds without antibiotic coverage. There was a 95 % success rate in wounds left open for 4 to 10 days in spite of positive bacterial cultures from the wound.¹²

Patzakis was the first to do a prospective, randomized study comparing the infectious rates for Penicillin with Streptomycin, Cephalothin and placebo.⁶⁸ The rates were: control 13.9%, Penicillin 9.7%, Cephalothin 2.3%. Unfortunately the study was not double-blinded and did not grade for severity of open fractures. Nonetheless, it is the first report showing a benefit of prophylactic antibiotics in these severe extremity injuries. Since Patzakis' study, the literature contains multiple reports comparing various antibiotic regimens for efficacy in reducing infections and durations of therapy. These studies do stratify for grade of open fracture.

B. Choice of antibiotic

The majority of studies contain populations of patients with various mechanisms of injury. Hansraj et al.²⁴ performed a non-blinded comparison of Ceftriaxone against Cefazolin in extra-articular bony injuries from gunshot wounds. The mean time between injury and initial antibiotic dose was 4 hours. All admission cultures were negative for growth and none of the patients subsequently developed clinical signs of infection. They concluded that the cost of therapy was significantly less with Ceftriaxone and resulted in a one day reduction in length of stay.²⁴ This study raises a question of whether low velocity missile injury to extra-articular cortical bone requires any prophylaxis at all. However, it does suggest single dose, long acting, antibiotics are cost effective in this patient population compared to shorter acting, first generation cephalosporins which require multiple dosing.

The benefit of gram negative coverage in gunshot wounds producing skeletal fractures was also evaluated in children.³² The majority of these wounds were produced by low velocity missiles. Forty- five patients (59%) received a first generation cephalosporin for 48 hours. None of these patients developed an infectious complication. The authors concluded that grade I and II open fractures produced by low velocity missiles in children only require antibiotics for 48 hours.

Hope and associates evaluated the role of antibiotics in children with open tibial fractures.³⁷ Despite broad spectrum antibiotics for at least 48 hours, the wound infection rate was 11%. However, the most important variable in these infections was felt to be the severity of the soft tissue injury rather than the antibiotic coverage.³⁷ In a similar review of open tibial fractures in children, Buckley reported a rate of wound infection of 7.3%, osteomyelitis 4.9% and pin track infection 20%.¹³ Antibiotics were administered for 48 hour intervals and repeated with subsequent wound debridement. They concluded the most important variable in reducing wound infection was utilizing delayed wound closure rather than primary closure.¹³ Patzakis and colleagues retrospectively reviewed their experience with various antibiotic regimens including Penicillin, Cephalothin, and Cefamandole as well as a control arm with no antibiotics.⁴⁴ They also looked at the infection rate for adults (7.2%) and pediatric patients (1.8%). The various infectious complication rates were: placebo 13.9%, Penicillin plus Streptomycin 10%, Cephalothin 5.6%, Cefamandole plus Tobramycin 4.5%. The duration of antibiotic therapy was not correlated with the reduction in infection rate. Thus, they concluded that for severely contaminated wounds broad spectrum antibiotics administered as soon as possible after injury should be initiated and continued for no more than 72 hours.⁴⁴

Other investigators have relied on wound cultures to direct antibiotic therapy. Robinson in a prospective study of open fractures reported 83% of the initial cultures as being positive.⁴⁵ More importantly, over 90% of the organisms identified in these cultures were sensitive to routine antibiotics (1^st generation cephalosporins). Four patients had persistent positive cultures at the time of a second debridement 24 hours after admission and all developed a deep wound infection. They concluded that sequential wound cultures facilitated antibiotic therapy in the management of open extremity fractures.

The importance of prophylactic antibiotic for open fractures of the knee, ankle, hand, digits and skull has also been evaluated and found to be beneficial.^{19,21,26,38,49,52,55,56,58,63} Benson et al. compared Clindamycin against Cefazolin and saw no difference in the infection rate with either agent.⁵⁷ This study demonstrates any antimicrobial agent with Staphylococcus aureus coverage is adequate effective prophylaxis for open fractures. Thus, there is adequate Class I and II data to document the benefit of prophylactic antibiotics in open extremity fractures. Agents effective against Staphylococcus aureus provide adequate prophylaxis for Grade I and II fractures.^57,61,66-68 In Grade III fractures, the addition of an aminoglycoside improves gram-negative coverage.^{13-15,17,22,25,33,37-39,44-46,50,51,59,60,62,64,65}

C. Duration of therapy

Multiple studies have demonstrated the interaction between antibiotic therapy and wound management.^{13,14,22,23,27,33,35,37,39,42,44,45,65,67} For Grade I and II fractures, wounds which are primarily closed, 24 hours of antibiotic coverage, when initiated within 4 hours of injury is adequate. Dellinger et al. observed no relation between the duration of antibiotic administration (6 or 24 hours, 3 or 5 days) and the risk of infection.^7,47 This was independent of the grade of the fracture. More importantly they identified the tibia being the most significant predictor of subsequent infection.

D. Route of antibiotic delivery

The majority of reports continue to utilize intravenous antibiotics for prophylaxis. Several investigators have utilized aminoglycocide-polymethylmethacrylate (PMMA) beads allow or in addition to parenteral antimicrobials.^{16,22,27,28,30,31,34,35,40} Ostermann et al. showed a significant reduction in infection rates for Grade II and III fractures with the addition of aminoglycoside-polymethylmethacrylate (PMMA) beads to parenteral antibiotics (3.7% versus 12%).²⁸ They concluded that adjuvant local antibiotic therapy decreases the incidence of late infection in Grade III open fractures. Unfortunately, this was not a randomized study. A similar conclusion was reached when PMMA beads were utilized in Type IIIc open fractures.³⁰ Henry and colleagues utilized the PMMA beads as a temporary coverage of soft tissue defects in addition to intravenous delivery. The observed wound infection rate was 5.3% and osteomyelitis 3.9% in 227 open fractures. They suggest that the PMMA beads are most useful for Grade III wounds where the bead pouch serves as a substitute for soft tissue coverage of the exposed bone and tendons. Again, this was a non-randomized study. The other question that this technique raises is whether there is a need for parenteral as well as local therapy. It is questionable whether the local therapy provides adequate tissue levels of antibiotic without systemic administration.

V. Evidentiary Table

This evidentiary table contains 56 articles which were utilized to formulate these guidelines. The data are listed in chronologic order by year of publication beginning with the most recent article. It includes 10 Class I articles, 9 Class II and 37 Class III references. The following data was retrieved and recorded from each article and is listed under the conclusion sections. The protocol design, the antibiotics utilized, infectious complications and the conclusions of the study.

V. Future Studies

There is a need to re-evaluate the current infection rate for long bone open fractures. These studies should specifically focus on the most difficult wound, ie. The grade IIIB tibial injury. Design should evaluate the effect of wound debridement, systemic and local antibiotics, duration and specific agents as well as cost analysis. Because of the relatively low rate of infection, a multi-institutional effort would allow a meaningful study to be completed in a short time period.

REFERENCES

1. Gustilo RB, Anderson JT: Prevention of infection in the treatment of one thousand and twenty-five open fractures of long bones. J Bone Joint Surg 1976; 58A:453.
2. Gustilo RB, Mendoza RM, Williams DN: Problems in the management of type III (severe) open fractures: A new classification of type III open fractures. J Trauma 1984;24:742.
3. Seligson D, Banis J, and Metheny L. Tibia terrible. In: Coombs R, Green S, Sarmiento AS, ed. External fixation and functional bracing. London: Orthotext, 1989:281-4.
4. Court-Brown CM: Antibiotic prophylaxis in orthopaedic surgery. Scand J Infect Dis Suppl 1990; 70:74.
5. Dellinger EP, Miller SD, Werta MJ, et al: Risk of infection after open fracture of the arm or leg. Arch Surg 1988;123:1320
6. Norden CW: A critical review of antibiotic prophylaxis and orthopedic surgery. Rev Infect Dis 1983; 5:928.
7. Dellinger EP. Antibiotic prophylaxis in trauma: penetrating abdominal injuries and open fractures. Rev Infect Dis 1991; 13:S847.
8. Oxman AD, Sackett DL, Guyatt GH. User’s guide to the medical literature. JAMA 1993; 270: 2093.
9. Cruse P: Wound infections: Epidemiology and clinical characteristics in surgical infectious diseases. ed Howard R. and Simmons R. Appleton and Lange, Norwalk, Conn. 1988, pp 319-329.
10. Orr H: The treatment of infected wounds without sutures, drainage tubes or antiseptic dressings. J Bone Joint Surg 1928;10:605.
11. Truetta J: War surgeries of extremities: treatment of war wounds and fractures. Brit Med J 1942;1:616.
12. Whelan T, Bucholz W, Gomez A: Management of war wounds. Advances in Surgery, ed. Welch C. Yearbook Medical Publishing, Chicago, 1968, pp. 227-351.

EVIDENTIARY TABLES