EAST PRACTICE MANAGEMENT GUIDELINES WORK GROUP:

UPDATE TO PRACTICE MANAGEMENT GUIDELINES FOR PROPHYLACTIC ANTIBIOTIC USE IN OPEN FRACTURES

William S. Hoff, MD, FACS¹, John A. Bonadies, MD, FACS²,                            Riad Cachecho, MD, FACS, FCCP³, Warren C. Dorlac, MD, FACS⁴

¹St. Luke's Health Network, Bethlehem, PA

²Hospital of St. Raphael, New Haven, CT

³Crozer Chester Medical Center, Upland, PA

⁴University of Cincinnati, Cincinnati, OH

Presented at the Twenty-first Annual Assembly of the Eastern Association for the Surgery of Trauma, January 19, 2008, Jacksonville, FL

I.          Statement of the Problem

An open fracture is defined as one in which the fracture fragments communicate through a break in the skin.  The presence of an open fracture either isolated or as part of a multiple-injury complex, increases the risk of infection and soft tissue complications.  In 1976, Gustilo described a system to classify open fractures based on the size of the associated laceration, the degree of soft issue injury, contamination and presence of vascular compromise.¹  In general, risk of infection and incidence of limb loss correlates with the Gustilo grade (Table 1).

II.          Process

Using a search methodology similar to Luchette, et al., a MEDLINE search was performed using the key words “open fractures” and “antibiotics”.²  This search was limited to articles published subsequent to the guidelines published by Luchette.  This search yielded a total of 49 articles.  Sixteen (16) articles were excluded for the following reasons: technical article (6), non-English publication (5), insufficient contribution to the project (2), involved non-extremity fractures (2), animal study (1).  Thirteen (13) secondary citations were obtained from bibliographies in the initial articles yielding 46 articles which were reviewed by the subcommittee.

Each article was reviewed and classified based on methodology described by the Agency for Healthcare Policy and Research of the U.S. Department of Health and Human Services as follows:

For purposes of this practice management guideline, review articles were classified as Class III.  Reviewers also determined whether the respective article was relevant to the purpose of the practice management guidelines.  Nineteen (19) studies were determined to be non-relevant and were excluded from further analysis; non-relevance was based on the following: poor methodology (11), inadequate study size (6), irrelevant purpose (2).

The remaining 27 articles were used to construct an evidentiary table which was analyzed to make final recommendations.

III.         Recommendations

1. Level I

·          Systemic antibiotic coverage directed at gram positive organisms should be initiated as soon as possible following injury.

·          Additional gram negative coverage should be added for grade III fractures.

·          High-dose penicillin should be added in the presence of fecal or potential clostridial contamination (e.g., farm-related injuries).

·          Fluoroquinolones offer no advantage compared with cephalosporin/aminoglycoside regimens and may have a detrimental effect on fracture healing.

2. Level II

• Antibiotics should be discontinued 24 hours after wound closure for grade I and II fractures.

• In grade III fractures, antibiotics should be continued for 72 hours following injury or not more than 24 hours after soft tissue coverage has been achieved.

• Single-dose aminoglycoside dosing is safe and effective for grade II and III fractures.

IV.        Scientific Foundation

In 1998, Dr. Fred Luchette presented the results of the EAST Practice Management Guidelines Workgroup at the Eleventh Annual Scientific Assembly.²  These guidelines were published in 2000 on the EAST website.  Based on a review of 54 articles published from 1975 to 1997, the workgroup offered three level I and two level II recommendations specific to choice of antibiotic coverage and duration of therapy.  The original guidelines recommend preoperative dosing with antibiotics as soon as possible after the injury has been sustained.  Antibiotics should be directed at gram positive organisms with additional gram negative coverage for grade III fractures.  In the presence of potential clostridial contamination, penicillin should also be initiated irrespective of fracture grade.

With regard to duration of antibiotic coverage, the original guidelines recommend that antibiotics be discontinued 24 hours after successful wound closure for grade I and grade II fractures.  For grade III fractures, antibiotics should be continued for 72 hours subsequent to the injury or not more than 24 hours subsequent to successful soft tissue coverage of the wound.

In 1999, DeLong published a case series designed to compare rates of infection as well as delayed union and nonunion in patients with open fractures based on the type of wound closure performed.³  Ninety patients with 119 open fractures were reviewed.  All patients received cefazolin plus gentamicin if severe contamination was identified.  Antibiotics were discontinued 2 to 3 days following the last surgical procedure.  Using this antibiotic regimen, the rate of deep wound infection or osteomyelitis was 7% irrespective of the wound management technique.  In a prospective study of 227 patients with open fractures, Vasenius compared clindamycin with cloxacillin.  Clindamycin was demonstrated to be effective in grade I and grade II fractures with infection rates of 3.3% and 1.8% respectively.  Unacceptably high rates of infection were reported in grade III fractures for both clindamycin (29.0%) and cloxacillin (51.8%).  This study demonstrates the efficacy of gram positive coverage for grade I and II fractures and confirms the need for additional gram negative coverage in higher grade fractures.⁴

In a study of pediatric patients with open forearm fractures, Greenbaum reported a 3% incidence of wound infections using an antibiotic regimen similar to that recommended by the original EAST guidelines.⁵  In a retrospective study by Yang, 91 patients with grade I open fractures received cefazolin.  Initial surgical debridement was not performed on an emergent basis and no infectious complications were documented in the study cohort.⁶

Citing several advantages of fluoroquinolones (e.g, oral administration, less nephrotoxicity, etc.), Patzakis performed a prospective study of ciprofloxacin in 163 patients with 171 open fractures: grade I (65); grade II (54); grade III (52).  Patients were randomized to an antibiotic regimen of ciprofloxacin or ceftazadime/gentamicin.  In grade I and II fractures, the infection rate for the ciprofloxacin group and the ceftazadime/gentamicin group was 5.8% and 6.0% respectively.  For grade III fractures, an unacceptably high rate of infection was demonstrated in the ciprofloxacin group (31%) compared with the ceftazadime/gentamicin group (7.7%).⁷  In response to a clinical observation that delayed union and nonunion were associated with ciprofloxacin, Huddleston published a laboratory investigation of the effect of this flouroquinolone on fracture healing.  Wistar rats with experimentally induced femur fractures were randomized to receive cefazolin, ciprofloxacin.  A third group received no antibiotics was used as a control group.  Radiographic, histologic and mechanical parameters all demonstrated inhibition of fracture healing in the ciprofloxacin group.⁸  Similarly, using a murine model, Holtom demonstrated a dose dependent cytotoxic effect of fluoroquinolones.⁹

In 1999, Sorger published a study comparing the efficacy of once-daily dosing of aminoglycosides with the traditional divided-dose regimen.  Two hundred nineteen patients with grade II or grade III open fractures all received standard surgical treatment of their fractures.  All patients received cefazolin but were randomized to receive gentamicin in divided-dose regimen (5 mg/kg divided twice daily) or once-daily (6 mg/kg).  While a statistical difference could not be demonstrated, infection rate in the once-daily patients was lower than in the patients receiving divided-dose (6.7% vs. 13.6%).¹⁰  In a preliminary study, Russel demonstrated safety and efficacy of once-daily aminoglycoside dosing in conjunction with cefazolin in the treatment of 16 patients with open tibia fractures.¹¹

V.        Summary

Based on a review of the literature published subsequent to their original presentation, the recommendations published in the original EAST guidelines remain valid.  Antibiotics are an important adjunct to the management of open fractures and should be initiated as soon as possible.  Gram positive coverage is recommended for grade I and grade II fractures.  Broader antimicrobial coverage is recommended for grade III fractures.

In spite of the potential clinical and resource advantages of fluoroquinolones, current research does not support their use and studies suggest these agents may impair fracture healing.  When required, aminoglycosides may be prescribed in a once-daily regimen.

VI.        Future Investigation

The available class I literature on fluoroquinolones has several limitations.  Not all studies utilized an open fracture model.  In addition, as these were animal studies, dosages and duration of therapy may not be equivalent to that which may be utilized clinically.  Therefore, given the significant advantages of this class of antibiotics over aminoglycosides, research should continue in an effort to demonstrate efficacy in a clinical model.  The systemic side effects of antibiotics may also be reduced through the use of local antibiotic therapy.  Future research should also consider the use of this modality in the acute phase of open fracture management.

VII.       References

1. Gustilo RB, Anderson JT.  Prevention of infection in the treatment of 1025 open fractures of long bones.  JBJS: 58A: 453-459, 1976.

2. Luchette FA, Bone LB, Born CT, et al.  EAST Practice Management Guidelines Workgroup: Practice management guidelines for prophylactic antibiotic use in open fractures.  Eastern Association for the Surgery of Trauma, http://www.east.org/tgp/openfrac.pdf, 2000.

3. DeLong WG, Jr., Born CT, Wei SY, et al.  Aggressive treatment of 119 open fracture wounds.  J Trauma 46: 1049-1054, 1999.

4. Vasenius J.  Clindamycin versus cloxacillin in the treatment of 240 open fractures.  A randomized prospective study.  Ann Chir Gynaecol 87: 224-228, 1998.

5. Greenbaum B.  Open fractures of the forearm in children.  J Orthop Trauma 15: 111-118, 2001.

6. Yang EC.  Treatment of isolated type I open fractures: is emergent operative debridement necessary?  Clin Orthop Relat Res 410: 269-294, 2003.

7. Patzakis MJ, Bains RS, Lee J, et al.  Prospective, randomized, double-blind study comparing single-agent antibiotic therapy, ciprofloxacin, to combination antibiotic therapy in open fracture wounds.  J Orthop Trauma 14: 529-533, 2000.

8. Huddleston PM, Steckelberg JM, Hanssen AD, et al.  Ciprofloxacin inhibition of experimental fracture healing.  JBJS 82A: 161-173, 2000.

9. Holtom PD, Pavkovic SA, Bravos PD, et al.  Inhibitory effects of the quinolone antibiotics trovafloxacin, ciprofloxacin, and levofloxacin on osteoblastic cells in vitro.  J Orthop Res 18: 721-727, 2000.

10. Sorger JI, Kirk PG, Ruhnke CT, et al.  Once daily, high dose versus divided low dose gentamicin for open fractures.  Clin Orthop 366: 197-204, 1999.

11. Russel GV, Jr.  Once daily high-dose gentamicin to prevent infection in open fractures of the tibial shaft: a preliminary investigation.  South Med J 94: 1185-1191, 2001.

Table 1: Open Fractures – Gustilo Classification¹

 UPDATE TO PRACTICE MANAGEMENT GUIDELINES FOR PROPHYLACTIC

ANTIBIOTIC USE IN OPEN FRACTURES: EVIDENTIARY TABLE

(R) – Review article