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Antibiotic Prophylaxis in the


Management of Open Fractures
A Systematic Survey of Current Practice and Recommendations

Yaping Chang, MSc Abstract


Mohit Bhandari, PhD, MD Background: Evidence with regard to antibiotic prophylaxis for patients
with open fractures of the extremities is limited. We therefore conducted a
Kan Lun Zhu, BHSc systematic survey addressing current practice and recommendations.
Reza Donald Mirza, MD Methods: We included publications from January 2007 to June 2017.
We searched Embase, MEDLINE, CINAHL, the Cochrane Central Registry
Downloaded from http://journals.lww.com/jbjsreviews by BhDMf5ePHKbH4TTImqenVKFjfEjHw8MEuMluX8dhfw8uzu1iQtgQcTJq9fqLe7I/XBNVGzAS8No= on 02/22/2019

Melody Ren, MD
of Controlled Trials (CENTRAL), and the Cochrane Database of Systematic
Sean Alexander Kennedy, MD Reviews for clinical studies and surveys of surgeons; WorldCat for textbooks;
Ahmed Negm, MSc, MD and web sites for guidelines and institutional protocols.

Neera Bhatnagar, MLIS Results: We identified 223 eligible publications that reported 100 clinical
practice patterns and 276 recommendations with regard to systemic
Faysal N. Naji, BHSc, MPH, MD antibiotic administration, and 3 recommendations regarding local anti-
Lazar Milovanovic, MD biotic administration alone. Most publications of clinical practice patterns
used regimens with both gram-positive and gram-negative coverage
Yutong Fei, PhD, MD and continued the administration for 2 to 3 days. Most publications
Arnav Agarwal, BHSc recommended prophylactic systemic antibiotics. Most recommendations
suggested gram-positive coverage for less severe injuries and administration
Rakhshan Kamran duration of 3 days or less. For more severe injuries, most recommendations
Sung Min Cho, BHSc suggested broad antimicrobial coverage continued for 2 to 3 days. Most
publications reported intravenous administration of antibiotics
Stefan Schandelmaier, MD
immediately.
Li Wang, PhD
Conclusions: Current practice and recommendations strongly support
Lin Jin, MPH, MD early systemic antibiotic prophylaxis for patients with open fractures of
the extremities. Differences in antibiotic regimens, doses, and durations
Shiyun Hu, PhD, MD
of administration remain in both practice and recommendations.
Yanping Zhao, PhD Consensus with regard to optimal practice will likely require well-
Luciane Cruz Lopes, PhD designed randomized controlled trials.
Clinical Relevance: The current survey of literature systematically provides
Mei Wang, MSc, MD
surgeons’ practice and the available expert recommendations from 2007 to
Brad Petrisor, MD 2017 on the use of prophylactic antibiotics in the management of open
Bill Ristevski, MD fractures of extremities.

Reed A.C. Siemieniuk, MD

O
Gordon H. Guyatt, MD pen fractures involve the other crush-type injuries1-4. In open frac-
protrusion of bone through tures, there is a higher risk of infection
skin resulting in skin and that may not only contribute to wound-
Investigation performed at the soft-tissue compromise. healing problems, but may also play an
Department of Health Research This may be the result of an inside-out type important role in the subsequent develop-
Methods, Evidence, and Impact, injury, as can be seen in high-energy or ment of nonunion and continued osseous
McMaster University, Hamilton,
Ontario, Canada
COPYRIGHT © 2019 BY THE Disclosure: There was no source of external funding for this study. The Disclosure of Potential
JOURNAL OF BONE AND JOINT Conflicts of Interest forms are provided with the online version of the article (http://links.lww.com/
SURGERY, INCORPORATED JBJSREV/A428).

JBJS REVIEWS 2019;7(2):e1 · http://dx.doi.org/10.2106/JBJS.RVW.17.00197 1


| Antibiotic Prophylax is in the Management of Open Fractu res

instability1,2,5-7. Preventing infection is RCTs have effectively addressed issues or single-center RCTs, cohort studies,
therefore of the utmost importance in such as the optimal choice of antibiotics, case-control studies, and single-arm
open fracture management. whether that choice differs with fracture studies that indicate the use of antibi-
Investigations have frequently type, or the optimal duration of antibi- otic prophylaxis among patients with
identified gram-positive bacteria, such otic administration. open fracture and with $80% of
as Streptococcus and Staphylococcus, as Under these circumstances, patients enrolled after December 31,
the most commonly found bacteria in guidelines become important, and cli- 2006; review articles; surveys of sur-
Gustilo type-I and II fractures. With nicians need to understand the nature geons with information regarding the
increasing severity of open fracture, and and range of advice that guidelines pro- use of antibiotic prophylaxis in open
with soil-contaminated wounds, gram- vide. To our knowledge, no systematic fracture management; orthopaedic
negative or mixed bacteria are more survey of antibiotic prophylaxis exists to textbooks; clinical practice guidelines;
likely to be present. Clinicians should inform practice or future research. We and institutional protocols provided on
consider using broader coverage in open therefore undertook a systematic survey web sites of trauma centers that ad-
fractures contaminated by fresh water with the goal of summarizing current dressed the management of open frac-
(Aeromonas and Pseudomonas) and practice and expert guidance in the use tures and provided guidance with
salt water (Vibrio)2,8. The association of antibiotic prophylaxis for open frac- regard to appropriate prophylactic
between the Gustilo classification and tures. The current article is thus not antibiotic regimens.
the organisms that colonize wounds may intended as a systematic review of We excluded publications ad-
have implications for the optimal choice the evidence-based use of antibiotics. dressing the use of antibiotics in patients
of antibiotics, which is the issue of con- Rather, it is intended as a systematic with known infections or human
cern in this article. survey of reports of surgeons’ practice in immunodeficiency virus or acquired
Surgeons can use several strategies the use of prophylactic antibiotics and immune deficiency syndrome (HIV/
to minimize the development of infec- a complementary systematic survey of AIDS) and publications restricted to
tion, including timely wound irrigation the available expert recommendations. pediatric injuries.
and debridement, timely fracture stabi- The scope of the study includes all
lization, and the early administration of published articles that describe practice Data Sources and Search Strategy
systemic antibiotics7,9,10. Given the and all published articles, textbooks, We identified relevant publications
certainty of contamination and the high guidelines, and institutional protocols using a systematic search of Embase,
rate of infection5, prophylactic antibi- that offer recommendations with regard MEDLINE, the Cumulative Index to
otics in open fracture care delivered to antibiotic prophylaxis. Nursing and Allied Health Literature
immediately after the injury have (CINAHL), the Cochrane Central
become routine11,12. The surgeon or Materials and Methods Registry of Controlled Trials (CEN-
emergency room doctor typically choo- We registered our study protocol with TRAL), and the Cochrane Database
ses the type of antibiotic, the route of PROSPERO (Prospective Register of of Systematic Reviews21. Keywords
delivery, and the duration. The antibi- Ongoing Systematic Reviews; identifier: included antibiotics, antimicrobial,
otic administration may differ depend- CRD42016053285) and reported the antibiotic prophylaxis, open fracture,
ing on department protocols and the results according to PRISMA (Preferred compound fracture, Gustilo-Anderson
surgeon’s preferences. Clinicians often Reporting Items for Systematic Reviews type, fracture fixation, nonunion, and
combine multiple antibiotics together and Meta-Analyses) recommendations infection and the names of specific
when there is a substantial risk that a (Fig. 1)20. antibiotics (see Appendix).
single agent would not provide antimi- We conducted a search for text-
crobial coverage against all infecting Eligibility Criteria books using WorldCat (the world’s
organisms13-17. We included publications over the last largest online catalog for textbooks,
Given these considerations, a vari- decade that include a section addressing www.worldcat.org) from 2007 to 2017.
ety of antibiotic regimens are reasonable; either or both of 2 questions: (1) what Keywords included orthop(a)edic sur-
the optimal regimen is most likely regimens (drug, dose, route of adminis- gery, orthop(a)edic operation, open
context-dependent. Systematic reviews tration, start time, and duration) are fracture, antibiotic prophylaxis, and
of randomized controlled trials (RCTs) clinicians using as prophylaxis, and (2) infection prevention.
are available and have established that what regimens are recommended in We consulted Canadian surgeons
there is moderate-quality evidence that publications? and their international orthopaedic col-
administration of antibiotics compared We searched and retrieved the leagues about sources of clinical practice
with no antibiotics appreciably reduces evidence from the following publica- guidelines and Internet-published pro-
wound infections18,19. There is a lack of tions that were published from January tocols addressing the management of
current evidence; to our knowledge, no 1, 2007, to June 30, 2017: multicenter open fractures. We conducted an open-

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Antibiotic Prophylax is in the Management of Open Fractures |

Fig. 1
Eligibility assessment PRISMA flow20 diagram. Cochrane SR 5 Cochrane Database of Systematic Reviews.

ended Google search with the key- lines Work Group (www.east.org), Study Selection and Data Abstraction
words trauma, injury, open fracture, Medscape (www.medscape.com), Before starting the eligibility review,
antibiotic, and (guideline or protocol). SurgWiki (www.surgwiki.com), reviewers conducted calibration exercises
We searched the web sites of the Agency Cambridge Orthopaedics (www. to ensure consistency. Reviewers worked
for Healthcare Research and Quality cambridgeorthopaedics.com), and in pairs, independently and in duplicate,
(www.ahrq.gov/gam/index.html), the OrthoBullets (www.orthobullets. screened titles and available abstracts, and
American Academy of Orthopaedic com/trauma/1004/open-fractures- retrieved the full text of potentially eligi-
Surgeons (www.aaos.org), the Ortho- management) for relevant clinical ble publications. For clinical practice
paedic Trauma Association (www.ota. practice guidelines published from guidelines and institutional protocols,
org), the Scottish Intercollegiate 2007 to 2017. reviewers directly screened full texts.
Guidelines Network (SIGN) (www. We checked the references of the Reviewers resolved disagreement by dis-
sign.ac.uk), the National Institute for included articles and relevant sections cussion or, if disagreement remained,
Health and Care Excellence (NICE) in included textbooks and guidelines through discussion with an arbitrator.
(www.nice.org.uk), the British Ortho- for any additional eligible publications. We assessed chance-corrected agreement
paedic Association (www.boa.ac.uk), We used the latest version of a textbook or in full-text eligibility judgments using the
the East Practice Management Guide- a guideline when .1 version was available. kappa statistic22.

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| Antibiotic Prophylax is in the Management of Open Fractu res

Reviewers, working in pairs, ex- probably should not, certainly should excluded as duplicates and an additional
tracted data independently from each not, and no opinion. 10,563 were excluded on the basis of
eligible data source. One reviewer ex- We summarized used or recom- review of title, contents, and index. We
tracted data, and the other double- mended antibiotic regimens. In many were unable to access the full text of 4
checked the results. One author checked instances, authors made statements with articles and 47 textbooks (Fig. 1).
all of the abstracted data. Abstracted data regard to prophylactic antibiotics, but Of the 910 articles, 439 textbooks,
included the strength of recommenda- did not specify the name of drugs or and 11 online guidelines that underwent
tions with regard to whether antibiotics whether they were referring to gram- full-text review, 754 articles, 377 text-
should be systematically given to positive coverage, gram-negative cover- books, and 6 online guidelines did not
patients with open fractures of the age, or both. When we summarized and address prophylactic antibiotics for
extremities, injury severity, prophylactic reported the proportion of antibiotic patients with open fracture of the
antibiotic regimen, dose, route of regimens used or recommended, we did extremities or did not describe evidence
administration, start time, duration, and not include in the denominator the after 2006, leaving a total of 223 eligible
type of evidence. reports in which authors specified nei- publications (156 articles, 62 textbook
ther drug names nor categories of drugs. chapters, and 5 online guidelines)
Data Summarization We reported the dose of antibiotics in a (Fig. 1).
We categorized all of the included descriptive way, as the dose in included There was a high level of agreement
information as a description of practice publications was too diverse to be for full-text eligibility selection of articles
or a recommendation. On the basis of effectively categorized. in electronic databases (kappa, 0.80);
the advice of orthopaedic surgeons, we We used Microsoft Excel to record the agreement with regard to full-text
combined injuries with a similar prog- the data and to make calculations for eligibility selection of textbooks, clinical
nosis from the primary articles, textbook sorting and summarization. practice guidelines, and institutional
chapters, and guidelines. Internal med- protocols was perfect (kappa, 1.0).
icine physicians categorized the pro- Results
phylactic antibiotic regimens and Study Identification Overall Characteristics of the
resolved disagreements through Our search identified 17,707 titles and Included Publications
discussion. abstracts from the electronic database Among the 223 included publications,
We categorized recommendations search; of these, 279 were excluded as 67 reported actual practice and 147
by injury severity groups with regard to duplicates and an additional 16,514 provided recommendations; 9 reported
whether antibiotics should be given to were excluded on the basis of review both practice and recommendations
patients with open fractures as follows: of title and abstract. We identified (Tables I and II). Three of the 147 rec-
must (i.e., strongly in favor), probably 11,691 textbooks from the search in the ommendations addressed local antibi-
should, possibly should, uncertain, WorldCat web site; of these, 642 were otic administration alone23-25.

TABLE I Distribution of Publications on Prophylactic Antibiotics for Patients with Open Fractures of
Extremities in Terms of Year of Publication*

Year Total Practice Only Practice and Recommendation Recommendation Only

2007 11 (4.9%) 2 (3.0%) 9 (6.1%)


2008 14 (6.3%) 14 (9.5%)
2009 15 (6.7%) 2 (3.0%) 1 (11.1%) 12 (8.2%)
2010 15 (6.7%) 6 (9.0%) 9 (6.1%)
2011 30 (13.5%) 11 (16.4%) 19 (12.9%)
2012 23 (10.3%) 5 (7.5%) 18 (12.2%)
2013 30 (13.5%) 11 (16.4%) 1 (11.1%) 18 (12.2%)
2014 37 (16.6%) 12 (17.9%) 5 (55.6%) 20 (13.6%)
2015 23 (10.3%) 9 (13.4%) 2 (22.2%) 12 (8.2%)
2016 19 (8.5%) 9 (13.4%) 10 (6.8%)
2017 6 (2.7%) 6 (4.1%)
Total 223 (100%) 67 (100%) 9 (100%) 147 (100%)

*The values are given as the number of publications, with the percentage in parentheses.

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Antibiotic Prophylax is in the Management of Open Fractures |

TABLE II Distribution of Publications on Prophylactic Antibiotics for Patients with Open Fractures of
Extremities in Terms of Location of Publication*

Continent Total Practice Only Practice and Recommendation Recommendation Only

North America 117 (52.5%) 25 (37.3%) 5 (55.6%) 87 (59.2%)


Europe 63 (28.3%) 17 (25.4%) 2 (22.2%) 44 (29.9%)
Asia 23 (10.3%) 17 (25.4%) 6 (4.1%)
Africa 6 (2.7%) 4 (6.0%) 1 (11.1%) 1 (0.7%)
Oceania 1 (0.4%) 1 (1.5%)
Multiple continents 13 (5.8%) 3† (4.5%) 1‡ (11.1%) 9§ (6.1%)
Total 223 (100%) 67 (100%) 9 (100%) 147 (100%)

*The values are given as the number of publications, with the percentage in parentheses. †One study was conducted in
North America and Europe, 1 study was conducted in North America and Asia, and 1 study was conducted in North
America and Oceania. ‡One study was conducted in North America and Asia. §Five evidence records were written by
authors from North America and Europe, 1 was written by authors from North America and Oceania, 1 was written by
authors from Europe and Oceania, 1 was written by authors from Europe and Asia, and 1 was written by authors from North
America, Europe, and Asia.

Three-fourths of the publications Thirty-eight publications specified local carriers were gentamicin, vanco-
were from 2011 or later (Table I). Just practice in lower-extremity injuries. mycin plus tobramycin if the cul-
over one-half were exclusively or jointly Only 24 specified the name of the anti- tures were negative or had not been
from North America (Table II). biotics; two-thirds used regimens with obtained28,31,37,54,87, and imipenem
broad bacterial coverage and all but 1 of or amikacin if Acinetobacter had been
Current Practice the others limited coverage to gram- isolated29. In 2 studies, the antibiotic
Type of Publications positive organisms61 (Table III; also see regimen was changed to target culture
Of 76 publications that recorded the Appendix). and sensitivity results29,83.
practice of systemic antibiotic prophy-
laxis in the treatment of open fractures, Dose Time to Antibiotic Administration
64 (84.2%) were primary clinical studies Nineteen of 100 reports of practice Start time in relation to injury: Thirty-
of single or multiple arms including included information regarding dose. eight reports specified the start time of
RCTs, cohort studies, case-control Two studies showed either weight-based antibiotic administration in relation
studies, case series, and case reports7,26-88, dosing95 or empirical administration83. to the time of injury. Of these, approx-
3 (3.9%) were surveys completed by The remainder reported use of regimens imately one-half gave the regimen
surgeons89-91, and 9 (11.8%) contained with ranges such as 1 to 2-g first- immediately after injury or in the
both primary data of patients and nar- generation cephalosporin every 6 to emergency department. All but 1 of
rative reviews and hence addressed both 8 hours. the remainder administered antibiotics
practice and recommendations14-17,92-96. within 1 hour, within 2 to 4 hours, or
Route of Administration within 10 to 12 hours after the injury.
Systemic Antibiotic Regimen Fifty-six reports of practice specified that One additional study showed adminis-
The 76 studies included 100 reports antibiotics were administered intrave- tration within 48 hours (i.e., within
of clinical practices by injury severity. nously or intravenously followed by oral 2 days, for low-velocity ballistic
Approximately one-third reported administration. The remainder did not fractures)89.
using only gram-positive coverage report the route of administration. Start time in relation to the surgical
(with or without coverage of methicillin- Sixteen reports mentioned that procedure: Seventeen reports speci-
resistant Staphylococcus aureus [MRSA] antibiotics were applied locally, fied the start time in relation to the
or anaerobic coverage), and another including antibiotic-infused equine surgical procedure. Of these, over
approximately one-tenth reported collagen sponges37, nanocrystalline one-half indicated that antibiotics
using only gram-negative coverage silver dressing50, antibiotic-impregnated were given at an unspecified time
(with or without anaerobic coverage) polymethylmethacrylate (PMMA) preoperatively33,44,56,59,60,78,88 or
(Table III). The remainder, just over beads28,31,42,83, a titanium alloy nail 1 hour16 or 30 minutes58 before skin
one-half, used regimens covering both with the alloy containing antibiotics39, incision. The remainder reported giv-
gram-positive and gram-negative and an impregnated en bloc cement ing antibiotics perioperatively27,57,
organisms (Table III). spacer93. The antibiotics impregnated in postoperatively52,71,94, or after the

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| Antibiotic Prophylax is in the Management of Open Fractu res

TABLE III Regimen in Practice for Prophylactic Antibiotics Systematically Given to Patients with Open Fractures of
Extremities*
Injury
Severity Not Soil, Marine,
Specified Gustilo Type Extremity‡ or Severely Gunshot Velocity
Antibiotic Regimen or for Contaminated
in Practice† All Levels I and II II and III III Upper Lower Wounds Low High

Gram-positive coverage§ 2 (16.7%) 3 (17.6%) 1 (5.0%) 2 (40.0%) 7 (18.4%)


Gram-positive and 1 (8.3%) 4 (23.5%) 2 (10.0%) 1 (50.0%)
anaerobic coverage#
Gram-positive and MRSA 1 (50.0%) 1 (33.3%)
coverage**
Gram-negative 3 (17.6%) 3 (15.0%)
coverage††
Gram-negative and 1 (2.6%)
anaerobic coverage
Broad coverage‡‡ 1 (8.3%) 7 (41.2%) 2 (100%) 7 (35.0%) 12 (31.6%) 1 (33.3%)
Broad and anaerobic 3 (15.0%) 1 (20.0%) 2 (5.3%)
coverage
Broad and MRSA 1 (8.3%)
coverage
Broad, MRSA, and 2 (5.3%) 1 (100%)
anaerobic coverage
Drug name not specified 7 (58.3%) 4 (20.0%) 2 (40.0%) 14 (36.8%) 1 (33.3%)
Total 12 (100%) 17 (100%) 2 (100%) 20 (100%) 5 (100%) 38 (100%) 2 (100%) 1 (100%) 3 (100%)

*The practice was determined from multicenter or single-center RCTs, cohort studies, case-control studies, single-arm studies (including case series), and surveys of surgeons that
indicate use of antibiotic prophylaxis among patients with open fracture. The values are given as the number of publications, with the percentage in parentheses. †Clindamycin was used
in patients with beta-lactam/penicillin allergies. ‡Upper-extremity fractures include open fractures of the hand, radius, and fingers for all Gustilo types of injury severity. Lower-extremity
fractures include open fractures of the tibia, femur, ankle, and calcaneus for all Gustilo types of injury severity. §Gram-positive coverage includes first and second-generation
cephalosporins (e.g., cefazolin, cephalexin, cefacidal, cefadroxil, cefuroxime), macrolide, ampicillin or amoxiclav, amoxicillin or co-amoxiclav, penicillin, and any combination of these
drugs. #Anaerobic coverage includes metronidazole, clindamycin, beta-lactam/beta-lactamase inhibitors (e.g., ampicillin/sulbactam, piperacillin/tazobactam), and carbapenems.
**MRSA coverage includes vancomycin or teicoplanin. ††Gram-negative coverage, in this case, refers to aminoglycosides (e.g., gentamicin, tobramycin, amikacin). ‡‡This indicates
broad-spectrum antibiotic coverage, including both gram-positive and gram-negative coverage. Such antibiotics include carbapenems (e.gs. ertapenem, meropenem), piperacillin/
tazobactam, third or/and fourth-generation cephalosporins (e.g., ceftriaxone), and any combination of antibiotics that include both gram-positive and gram-negative coverage.

operation if there were clinical indi- Practice proved to be similar over recommendations, approximately 90%
cations of infection and a positive time and across continents. had language consistent with a strong
wound culture as a treatment of recommendation for prophylactic sys-
infection29. Current Recommendations temic antibiotics to prevent wound
Duration: Fifty-one reports speci- Type of Publications infection, irrespective of injury severity.
fied the duration of antibiotic adminis- Of 153 publications (9 of which re- For open fractures of the upper and
tration. One study that investigated 66 ported both practice and recommenda- lower extremities, approximately 95%
surgeons’ attitudes toward prophylactic tions) that provided recommendations of recommendations strongly suggested
antibiotics showed that most respon- for systemic antibiotic prophylaxis in the use of antibiotics over no antibiotics.
dents chose a single dose16. For less the management of open fractures, 61 There was a unanimous consensus that
severe injuries, Gustilo type-I and II (39.9%) were textbook chapters97-157, antibiotic prophylaxis must be used for
open fractures, approximately one- 15 (9.8%) were clinical practice Gustilo type-III fractures, wounds that
fourth of reports specified antibiotic use guidelines158-172, 70 (45.8%) were had come into contact with soil or water,
for #1 day14,63,64, almost one-half review articles2,3,6,18,19,92,94,96,173-234, severely contaminated wounds, and
specified it for 2 to 3 days7,54,66,67,96, 3 (2.0%) were case series that provided high-velocity gunshot wounds or gun-
and the remainder specified it for 4 to 7 recommendations17,93,95, and 4 (2.6%) shot wounds in which the velocity was
days86,91. For more severe injuries, were surveys of surgeons14-16,235. not specified (see Appendix).
Gustilo type-III open fractures, one-half
of the reports specified that they gave Level of Recommendations Recommended Systemic Antibiotic
antibiotics for 2 to 3 days, one-fourth The 153 eligible publications provided Regimen
gave antibiotics for 4 to 7 days, and 276 recommendations addressing sys- The included publications reported 276
one-fourth gave antibiotics for .7 days temic antibiotic administration by cat- recommendations for varying injury
(Table IV). egory of injury severity. Of the 276 severities. For Gustilo type-I and II open

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TABLE IV Duration of Antibiotics in Practice for Prophylactic Antibiotics Systematically Given to Patients with Open
Fractures of Extremities*
Soil, Marine,
Duration of Injury Severity Gustilo Type Extremity† or Severely Gunshot Velocity
Antibiotics Not Specified Contaminated
in Practice or for All Levels I and II II and III III Upper Lower Wounds Low High

#1 day 1 (8.3%) 3 (17.6%) 2 (40.0%) 4 (10.5%)


2 to 3 days 1 (8.3%) 5 (29.4%) 1 (50.0%) 4 (20.0%) 8 (21.1%) 1 (33.3%)
4 to 7 days 1 (8.3%) 3 (17.6%) 2 (10.0%) 7 (18.4%) 1 (50.0%)
.7 days 2 (10.0%) 5 (13.2%)
Not 9 (75.0%) 6 (35.3%) 1 (50.0%) 12 (60.0%) 3 (60.0%) 14 (36.8%) 1 (50.0%) 1 (100%) 2 (66.7%)
specified
Total 12 (100%) 17 (100%) 2 (100%) 20 (100%) 5 (100%) 38 (100%) 2 (100%) 1 (100%) 3 (100%)

*The values are given as the number of publications, with the percentage in parentheses. †Upper-extremity fractures include open fractures of the hand, radius, and fingers
for all Gustilo types of injury severity. Lower-extremity fractures include open fractures of the tibia, femur, ankle, and calcaneus for all Gustilo types of injury severity.

fractures, approximately three-fourths negative coverage with antibiotics. For contaminated wounds, three-fourths rec-
recommended gram-positive coverage more severe open fractures, most rec- ommended broad coverage (Table V).
(with or without anaerobic coverage). ommendations favored broad antimi- Twenty-eight publications spe-
The remainder recommended regimens crobial coverage. For open fractures that cifically addressed lower-extremity
that we classified as broad coverage, had come into contact with soil or a injuries and made 34 recommenda-
including both gram-positive and gram- marine environment, and/or for severely tions for various injury severities.

TABLE V Regimen in Recommendations for Prophylactic Antibiotics Systematically Given to Patients with Open Fractures
of Extremities*
Injury
Severity
Not Soil, Marine, Gunshot Velocity
Specified Gustilo Type Extremity‡ or Severely
Recommended or for Contaminated Not
Drugs† All Levels I and II II and III III Upper Lower Wounds Specified Low High

Gram-positive 13 34 (68.0%) 9 (26.5%) 9 (22.0%) 1 (50.0%) 3 (50.0%) 6 (42.9%)


coverage§ (18.1%)
Gram-positive and 2 (4.0%) 1 (7.1%)
anaerobic coverage#
Gram-positive and 1 (1.4%) 1 (2.4%)
MRSA coverage**
Gram-negative 1 (1.4%) 2 (4.0%) 5 (10.9%) 1 (2.9%)
coverage
Broad coverage†† 14 10 (20.0%) 6 (85.7%) 35 (76.1%) 9 (26.5%) 26 (63.4%) 1 (50.0%) 1 (16.7%) 5 (35.7%)
(19.4%)
Broad and anaerobic 3 (4.2%) 1 (2.0%) 1 (14.3%) 3 (6.5%) 1 (2.9%) 4 (9.8%) 1 (7.1%)
coverage
Broad and MRSA 1 (2.2%) 1 (2.4%)
coverage
Broad, MRSA, and 5 (6.9%) 3 (8.8%)
anaerobic coverage
Drug name not 35 1 (2.0%) 2 (4.3%) 4 (100%) 11 (32.4%) 2 (33.3%) 1 (7.1%)
specified (48.6%)
Total 72 (100%) 50 (100%) 7 (100%) 46 (100%) 4 (100%) 34 (100%) 41 (100%) 2 (100%) 6 (100%) 14 (100%)

*The recommendation was determined from review articles, surveys of surgeons, guidelines, textbooks, and some clinical studies if they made recommendations. The values are given as the number of
publications, with the percentage in parentheses. †Several authors of original sources recommended clindamycin as an alternative to beta-lactams in patients who are allergic to beta-lactams or in
patients with suspected Group A Streptococcus infections. ‡Upper-extremity fractures include open fractures of the radius, humerus, and ulna for all Gustilo types of injury severity. Lower-extremity
fractures include open fractures of the tibia, femur, knee, foot and ankle, forefoot, phalanx, and calcaneus for all Gustilo types of injury severity. §Gram-positive coverage includes first and second-
generation cephalosporins (e.g., cefazolin, cephalexin, cefamandole, cefuroxime, cephradine), cloxacillin or flucloxacillin or dicloxacillin, erythromycin, ampicillin or augmentin, amoxicillin or co-
amoxiclav, penicillin, high-dose penicillin, penicillin G (benzylpenicillin) and any combination of these drugs. #Anaerobic coverage includes metronidazole, clindamycin, beta-lactam/beta-lactamase
inhibitors (e.g., ampicillin/sulbactam, piperacillin/tazobactam), and carbapenems. **MRSA coverage includes vancomycin or teicoplanin. Gram-negative coverage, in this case, refers to aminogly-
cosides (e.g., gentamicin, tobramycin, amikacin). ††This refers to broad-spectrum antibiotic coverage, including both gram-positive and gram-negative coverage. Such antibiotics include carbapenems
(e.g., ertapenem, meropenem), meronem, piperacillin/tazobactam, third or/and fourth-generation cephalosporins (e.g., ceftazidime, ceftriaxone, cefotaxime), and any combination of antibiotics that
include both gram-positive and gram-negative coverage.

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| Antibiotic Prophylax is in the Management of Open Fractu res

TABLE VI Duration of Antibiotics in Recommendations for Prophylactic Antibiotics Systematically Given to Patients with
Open Fractures of Extremities*
Recommended Soil, Marine, Gunshot Velocity
Duration of Injury Severity Gustilo Type Extremity† or Severely
Antibiotic Not Specified Contaminated Not
Administration or for All Levels I and II II and III III Upper Lower Wounds Specified Low High

#1 day 14 (19.4%) 17 (34.0%) 1 (14.3%) 1 (25.0%) 4 (11.8%) 1 (50%) 1 (16.7%)


2 to 3 days 5 (6.9%) 17 (34.0%) 2 (28.6%) 17 (37.0%) 13 (38.2%) 6 (14.6%) 1 (50%) 2 (33.3%) 9 (64.3%)
4 to 7 days 3 (4.2%) 10 (21.7%) 1 (2.9%) 4 (9.8%)
.7 days 1 (2.2%) 1 (25.0%) 3 (8.8%)
Not specified 50 (69.4%) 16 (32.0%) 4 (57.1%) 18 (39.1%) 2 (50.0%) 13 (38.2%) 31 (75.6%) 3 (50.0%) 5 (35.7%)
Total 72 (100%) 50 (100%) 7 (100%) 46 (100%) 4 (100%) 34 (100%) 41 (100%) 2 (100%) 6 (100%) 14 (100%)

*The values are given as the number of publications, with the percentage in parentheses. †Upper-extremity fractures include open fractures of the radius, humerus, and ulna for all Gustilo types of injury
severity. Lower-extremity fractures include open fractures of the tibia, femur, knee, foot and ankle, forefoot, phalanx, and calcaneus for all Gustilo types of injury severity.

Approximately 40% each suggested a spacers and cement impregnated or administration. For less severe injuries,
broad regimen or limiting coverage to mixed with heat-stable powered Gustilo type-I and II open fractures,
gram-positive organisms (Table V; see antibiotics of tobramycin and/or one-half suggested antibiotics for
Appendix). vancomycin97-105,180-185. A typical #1 day, and the remainder suggested
recommended ratio of antibiotics to antibiotics for 2 to 3 days. For Gustilo
Dose cement was 3.6 g of tobramycin to 40 g type-III fractures, approximately 60%
Approximately one-fourth of publica- of PMMA234. Additional suggestions suggested 2 to 3 days (some recom-
tions offered suggestions with regard to included BonyPid (PolyPid), beta- mendations suggested 72 hours total or
antibiotic dosing. Some gave general tricalcium phosphate granules coated 24 hours after wound closure, whichever
suggestion with regard to dose, such with BonyPid, which releases doxycy- comes first); of the remainder, over one-
as “adjusted to weight and renal cline at constant rate93. third suggested 4 to 7 days, and 1 sug-
clearance.”95,105,122 Others provided gested .7 days (Table VI).
drug-specific dose recommendations, Time to Antibiotic Administration Recommendations did not differ
for example, intravenous administration In relation to injury: Approximately appreciably by year of publication or
of 1 to 2 g of cefazolin every 6 to 8 hours one-half of the 276 recommendations geographic location.
for Gustilo type-I and II fractures, or made suggestions with regard to the
600 to 900 mg of clindamycin every 8 optimal time to antibiotic initiation after Discussion
hours via intravenous administration or injury or presentation to the hospital. We have provided a comprehensive over-
450 mg of clindamycin every 4 hours if Over one-half recommended that anti- view of the actual practice and recom-
patients were allergic to cephalosporin or biotics be administrated immediately mendations for primary antimicrobial
penicillin104,170, and adding 3 to 5 mg/ after the injury or on arrival to the hos- prophylaxis in patients with open extremity
kg/day of aminoglycoside for Gustilo pital. Of the remainder, most recom- fractures published from 2007 to 2017.
type-III fractures and further adding mended giving antibiotics within 3 Information about clinical practice
penicillin, 2 million units every 4 hours, hours of the injury. patterns showed that clinicians almost
for farm contamination109,147. In relation to the surgical procedure: always used broad-spectrum antibiotics
Less than one-tenth of the recommenda- rather than antibiotics with only reliable
Route of Administration tions addressed the timing of antibiotic gram-positive coverage, regardless of
Approximately one-half of the recom- administration in relation to the surgical injury severity (Table III).
mendations did not specify the route procedure. Of these, two-thirds recom- The most important difference
of administration. Of those that did, mended that antibiotics be administered between recommendations and practice
almost all recommended intravenous 1 or 2 hours prior to the surgical procedure, was that, when authors made recom-
administration. Approximately one- one-fourth recommended administration mendations for Gustilo type-I or II open
fourth recommended local antibiotics during the surgical procedure or fractures as a group, a majority recom-
in addition to systemic antibiotics. perioperatively118,172, and about one- mended restricting antibiotic use to
Recommendations for local use tenth suggested antibiotic adminis- agents with exclusively gram-positive
included delivery of antimicrobials tration postoperatively 94,228. coverage (Table V). Authors who
through antibiotic-impregnated Duration: Approximately one-half made recommendations for specific
PMMA beads or bead pouches, PMMA of the recommendations specified or antibiotics to cover gram-positive orga-
chains, PMMA strings, or PMMA addressed the duration of antibiotic nisms varied greatly in their suggestions,

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Antibiotic Prophylax is in the Management of Open Fractures |

including first and second-generation porting in the eligible articles. Most (adverse effects) and to society (antimi-
cephalosporins (e.g., cefazolin, cephalexin, included studies in our systematic survey crobial resistance in the community, an
cefamandole, cefuroxime, cephalexin, or were narrative reviews that made practice increasing concern globally).
cephradine), as well as anti-staphylococcal recommendations. Recommendations did The resolution of these issues,
penicillins (e.g., cloxacillin, flucloxacillin, not provide consistent, comprehensive, in particular, the degree of coverage
or dicloxacillin), a macrolide (e.g., eryth- and detailed descriptions in standard required, will require well-designed
romycin), ampicillin, amoxicillin, and formats that included drug, dose, route RCTs. Such studies should address
penicillin. of administration, start time, and dura- the limitations of previous studies by
A minority of authors (approxi- tion. Details were even more likely to be ensuring concealed randomization,
mately one-fifth) suggested, in contrast, absent in the reports of experience in blinding, complete follow-up, and doc-
broad antimicrobial coverage with clinical practice, observational studies, umentation of adverse reactions to anti-
activity against both gram-positive and and RCTs. This is understandable given biotics, and describing the nature of the
gram-negative organisms using agents that antibiotic use was not the focus of infections that occur (e.g., superficial or
such as carbapenems (e.g., ertapenem these articles. deep). Providing definitive guidance will
and meropenem), piperacillin/tazo- Our previous systematic review of also require that the trials be large, mul-
bactam, third or/and fourth-generation RCTs addressing the use of antibiotic ticenter studies sufficiently powered to
cephalosporins (e.g., ceftazidime, cef- prophylaxis compared with no prophy- provide definitive results that are broadly
triaxone, and cefotaxime), beta-lactams laxis suggested that antibiotics reduce applicable. In the interim, clinicians can
with a beta-lactamase inhibitor (e.g., the risk of infection, supporting both attend to the guidance offered, being
amoxicillin plus clavulanic acid, piper- practice and recommendations18. The aware that there is disagreement and the
acillin plus tazobactam, or ampicillin RCTs that compared prophylaxis with current best available evidence does not
plus clavulanic acid), or any combina- no prophylaxis used antibiotics with clearly support any particular approach.
tion of antibiotics that included reliable gram-positive coverage but no reliable
gram-positive and gram-negative cover- gram-negative coverage (first-genera- Appendix
age for both less and more severe injuries tion cephalosporins and penicillins). The MEDLINE title and abstract search
(such suggestions were thus more in Trials comparing longer and shorter strategy for the effects of antibiotic pro-
keeping with practice). All recommenda- regimens (1 day compared with 3 to 5 phylaxis in patients with open fracture
tions with available information suggested days) have failed to demonstrate any and tables showing the regimen in
a duration of #3 days (Tables V and VI). benefit with longer durations, based on practice for prophylactic antibiotics
When authors grouped Gustilo low to moderate-quality evidence. Only systematically given to patients with
type-II and III fractures together, over single studies have compared different open fractures of the lower extremities
90% suggested using broad coverage antibiotic regimens, and sample sizes by injury severity, the level of recom-
with reliable activity against both gram- have been too small for such studies to mendations about prophylactic systemic
positive and gram-negative organisms. be informative. The differences in rec- antibiotic therapy for patients with open
This was also true for wounds with soil ommendations with regard to which fractures of the extremities, and the regimen
or marine contamination (Table V). antibiotic to use are therefore understand- in recommendations for prophylactic anti-
The strengths of the present study able; the evidence provides little justifi- biotics systematically given to patients with
include explicit eligibility criteria, a cation for one regimen over another. open fractures of the lower extremities by
comprehensive search for relevant pri- Several key questions remain injury severity are available with the online
mary clinical studies, review articles unresolved with regard to primary pro- version of this article as a data supplement at
including many traditional and “gray” phylaxis with antibiotics in patients with jbjs.org (http://links.lww.com/JBJSREV/
literature (that is, not formally published open fractures. Whether there is any A429).
in books or journals and thus not benefit of broad compared with targeted
searchable through the indexed data- antimicrobial coverage or of coverage for NOTE:
bases) sources, clinical practice guidelines specific pathogens like MRSA or Pseu- The authors thank the following colleagues
in all languages, and duplicate assessment domonas remains uncertain, in general for their contribution to their research:
of eligibility with a high level of agreement. or in particular situations. This is also the Joan Burri, Sun Makosso, Yuan Zhang,
To our knowledge, this study represents case for whether administration can wait Yong Fang Zhu, and Miriam Beatty.
the first systematic survey addressing both until after obtaining reliable cultures or
what studies show in terms of use of anti- the sensitivity results of such cultures, Yaping Chang, MSc1,
biotics in prophylaxis in open fractures and and for the optimal duration of prophy- Mohit Bhandari, PhD, MD1,
Kan Lun Zhu, BHSc1,
what experts recommend. laxis. The use of broad-spectrum antibi- Reza Donald Mirza, MD1,
The limitations of our study were otics and antibiotics for longer durations Melody Ren, MD2,
primarily related to deficiencies in re- comes with notable harms to the patient Sean Alexander Kennedy, MD2,

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| Antibiotic Prophylax is in the Management of Open Fractu res

Ahmed Negm, MSc, MD1, E-mail address for Y. Chang: 3. Ali AM, Noyes D, Cogswell LK. Management
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Faysal N. Naji, BHSc, MPH, MD1,
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Lin Jin, MPH, MD1, 0000-0002-0576-4208 systemic and local antibiotics in the treatment
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Shiyun Hu, PhD, MD6, ORCID iD for M. Ren: Apr;48(2):137-53. Epub 2017 Jan 30.
Yanping Zhao, PhD7, 0000-0002-9687-5631
7. Petrisor B, Sun X, Bhandari M, Guyatt G, Jeray
Luciane Cruz Lopes, PhD8, ORCID iD for S.A. Kennedy: KJ, Sprague S, Tanner S, Schemitsch E, Sancheti P,
Mei Wang, MSc, MD1, 0000-0002-4970-8152 Anglen J, Tornetta P, Bosse M, Liew S, Walter S;
Brad Petrisor, MD1, ORCID iD for A. Negm: FLOW Investigators. Fluid Lavage of Open
Bill Ristevski, MD1, 0000-0001-5849-1402 Wounds (FLOW): a multicenter, blinded, factorial
pilot trial comparing alternative irrigating
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ORCID iD for F.N. Naji: 8. Zhang M, Chen YZ, Huang YQ, Huang XX.
1Department of Health Research Methods, 0000-0002-8926-6416 Selection of antibiotics in open fracture. Chin J
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of Medicine, Dalhousie 0000-0002-6806-1593
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University, Halifax, Nova Scotia, Canada ORCID iD for L.C. Lopes: Browner BD; Evidence-Based Quality Value and
0000-0002-3684-3275 Safety Committee Orthopaedic Trauma
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