Clinical Microbiology and Infection 26 (2020) 572e578

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Clinical Microbiology and Infection

journal homepage: www.clinicalmicrobiologyandinfection.com

Narrative review

Pathogenesis and management of fracture-related infection

M. Depypere 1, 11, *, M. Morgenstern 2, R. Kuehl 3, E. Senneville 4, T.F. Moriarty 5,
W.T. Obremskey 6, W. Zimmerli 7, A. Trampuz 8, K. Lagrou 1, 10, W-J. Metsemakers 9, 11
1)
Department of Laboratory Medicine, University Hospitals Leuven, Belgium
2)
Department of Orthopaedic and Trauma Surgery, University Hospital Basel, Switzerland
3)
Department of Infectious Diseases and Hospital Epidemiology, University Hospital Basel, Switzerland
4)
Department of Infectious Diseases, Gustave Dron Hospital, University of Lille, Lille, France
5)
AO Research Institute, Davos, Switzerland
6)
Department of Orthopaedic Surgery and Rehabilitation, Vanderbilt University Medical Center, Nashville, TN, USA
7)
Interdisciplinary Unit for Orthopaedic Infections, Kantonsspital Baselland, Liestal, Switzerland
8)
Charit
€tsmedizin Berlin, Corporate Member of Freie Universita
e e Universita €t Berlin, Humboldt-Universita
€t zu Berlin, and Berlin Institute of Health, Centre
for Musculoskeletal Surgery, Berlin, Germany
9)
Department of Trauma Surgery, University Hospitals Leuven, Belgium
10)
Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium
11)
Department of Development and Regeneration, KU Leuven, Belgium

a r t i c l e i n f o a b s t r a c t

Article history: Background: Both fracture-related infections (FRIs) and periprosthetic joint infections (PJIs) include or-
Received 23 May 2019 thopaedic implant-associated infections. However, key aspects of management differ due to the bone and
Received in revised form soft tissue damage in FRIs and the option of removing the implant after fracture healing. In contrast to
9 August 2019
PJIs, research and guidelines for diagnosis and treatment in FRIs are scarce.
Accepted 10 August 2019
Available online 22 August 2019
Objectives: This narrative review aims to update clinical microbiologists, infectious disease specialists
and surgeons on the management of FRIs.
Editor: L. Leibovici Sources: A computerized search of PubMed was performed to identify relevant studies. Search terms
included ‘Fracture’ and ‘Infection’. The reference lists of all retrieved articles were checked for additional
Keywords: relevant references. In addition, when scientific evidence was lacking, recommendations are based on
Antimicrobial therapy expert opinion.
Consensus guidelines Content: Pathogenesis, prevention, diagnosis and treatment of FRIs are presented. Whenever available,
Diagnosis specific data of patients with FRI are discussed.
Diagnostic criteria
Implications: Management of patients with FRI should take into account FRI-specific features. Treatment
Fracture
pathways should implement a multidisciplinary approach to achieve a good outcome. Recently, inter-
Fracture-related infection
Infection national consensus guidelines were developed to improve the quality of care for patients suffering from
Treatment this severe complication, which are highlighted in this review. M. Depypere, Clin Microbiol Infect
2020;26:572
© 2019 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All
rights reserved.

Introduction than in uninfected patients. Length-of-stay is the most important

Fracture-related infection (FRI) is a major complication in
musculoskeletal trauma surgery [1]. Recent studies show that
median costs per patient are six to seven times higher in infected
* Corresponding author. Melissa Depypere, Department of Laboratory Medicine,
University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium.
E-mail address: melissa.depypere@uzleuven.be (M. Depypere).
driver for total healthcare costs [2,3]. Furthermore, a recent sys-
tematic review focusing on chronic/late onset FRI stated that
recurrence of disease occurs in 6e9%, leading to amputation of the
affected limb in 3e5% [4].
Whereas published data on periprosthetic joint infection (PJI) is
extensive, published consensus guidelines on diagnosis and treat-
ment of FRI are still lacking. Thus, finding an optimal treatment
strategy is a challenge for surgeons, clinical microbiologists and
infectious disease specialists. Although both are implant-related

https://doi.org/10.1016/j.cmi.2019.08.006
1198-743X/© 2019 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
 M. Depypere et al. / Clinical Microbiology and Infection 26 (2020) 572e578
‘biofilm’ infections, management strategies for PJI cannot be
completely extrapolated to patients with FRI [5]. The main differ-
ence to the management of PJI is the fact that fracture fixation
devices can be removed without loss of function after osseous
healing [5]. Therefore, antibiotic suppression until bone consoli-
dation can be a curative option in patients with FRI [6]. Further-
more, similarly to PJI, FRI can manifest in a wide variety of clinical
scenarios. However, for FRI there are not only multiple
anatomical locations, but also multiple fracture patterns,
different degrees of soft tissue injury as well as different
patient conditions (poly-vs. isolated trauma) [7].
The aim of this narrative review is to summarize the current
literature on diagnosis and treatment concepts for FRI after frac-
tures of the extremities and pelvis.
Pathogenesis
Biofilm formation on the surface of foreign material is crucial in
the pathogenesis of FRI [8]. Microorganisms in a biofilm survive
much higher antibiotic concentrations than planktonic ones and,
therefore, systematically applied antibiotics mostly do not reach
the necessary therapeutic levels [9]. For this reason, successful
management of FRI requires a combination of surgical and anti-
microbial treatment [5,6,8].
FRI generally occurs exogenously due to the trauma itself (e.g.
open fracture), during insertion of the fixation device or during
disturbed wound healing or late soft tissue coverage in cases of
open fractures. Haematogenous infections are rare [8,10]. Table 1
gives an overview of the most commonly identified microorgan-
isms causing FRI [11e13]. Polymicrobial infections are frequent
(20e35%), and mainly occur in patients with open fractures [6,11].
Time is an important aspect in the pathogenesis of FRI for the
following reasons [5]. First, maturation of biofilms occurs over the
course of weeks and determines the efficacy of antimicrobial
therapy [14]. Second, fracture healing leading to bony consolida-
tion is crucial for cure of infection and takes place over the course
of weeks to months. Third, the extent of bone involvement needs
consideration when developing a treatment strategy. Preclinical
models have shown that within the first 2 weeks after fracture
fixation, the bone does not show signs of osteomyelitis or
osteolysis, despite the presence of bacteria on the implant [5].
Over the course of the following weeks, histological signs become
present. Currently, many classifications are based on these three
factors and on time in general. Willenegger and Roth [15] classi-
fied early-, delayed- and late-onset infections, occurring within 3,
3e10 and > 10 weeks after initial fracture fixation. Other authors
proposed a limit of 6 weeks after fracture fixation to differentiate
between acute and chronic infections [16]. At the present time,
classifying FRIs based on any of these time related cut-offs remains
arbitrary.
Prevention
Infection rates after internal fixation ranges from 1e2% (closed
fractures) up to 30% (open fractures), and are higher than elective
joint replacement [17].
The risk of developing an FRI is multifactorial and depends on
the location and severity of the injury, the extent of concomitant
injuries and on the host's physiology [1,5]. Several risk factors for
infection have been identified, such as male gender, diabetes mel-
litus, smoking, polytrauma, lower extremity fractures and injury
severity (according to the GustiloeAnderson classification)
[18e21].
To date, uniformly accepted guidelines related to prevention of
infection in fracture care are unavailable [1,17,19,22]. However, a
573
recent consensus conference addressed this issue and formulated
recommendations [23]. Specifically in high-risk patients (i.e. open
fractures), three major areas seem to be important: soft tissue
coverage, and systemic and local antibiotic therapy. First, experts
agree that early soft tissue coverage is a key aspect in infection
prevention. Guidelines recommend that open fracture wounds
should preferably be covered within 72 hr, and no later than 7 days
[24]. A delay of 1 week in soft tissue coverage following debride-
ment may increase the risk for recurrent infection [23]. Second, it is
accepted that early administration of prophylactic antibiotics has a
protective effect with respect to FRI [25]. First-generation cepha-
losporins are recommended, with only limited evidence for the
additional administration of an antibiotic with broad-spectrum
Gram-negative coverage in case of severe soft tissue damage (i.e.
GustiloeAnderson type III injuries) [23,26e28]. In patients with
closed fractures antibiotic prophylaxis is limited to a single dose
before surgery [29]. In patients with GustiloeAnderson type IeII
injuries, duration should not exceed 24 hr. In patients with
GustiloeAnderson type III injuries the duration of pre-emptive
therapy is not clear, owing to a lack of comparative studies. How-
ever, it should not exceed 72 hr. Finally, in case of open fractures,
systemic antibiotics alone are often not sufficient because the
damage to the surrounding tissues and blood vessels, by which
systemic antibiotics would normally reach the tissueeimplant
interface. A recent meta-analysis by Morgenstern et al. [30]
showed a significant risk reduction of infection when using pro-
phylactic additional local antibiotics, mainly polymethyl methac-
rylate (PMMA; bone cement), for open fractures. However, because
of limited data, future studies on the role of local antimicrobials in
patients with open fractures are necessary [19,23,30].
Diagnosis
The lack of a clear definition of FRI hampered interpretation of
research in the field [31]. Therefore, members of the FRI
Consensus group published, and recently updated, a definition of
FRI based on diagnostic criteria [7,32]. Two levels of certainty of
diagnostic features were defined. Criteria could be either confir-
matory (infection definitively present) or suggestive for FRI
(Table 2) [7,32].
Clinical signs
According to two systematic reviews, purulent drainage and
wound dehiscence/breakdown are confirmatory signs of infection,
because the implant communicates with the skin microbiome
[4,33]. Other local clinical signs such as pain, heat, redness and
swelling are only suggestive [7].
Serum inflammatory markers
In musculoskeletal trauma patients, these diagnostic tests
should be interpreted with caution [7]. A secondary rise after initial
decrease or an otherwise unexplained consistent elevation over a
Table 1
Most common microorganisms in fracture-related infection [11,12]
Microorganism Frequency (%)
Staphylococcus aureus 30e42%
Coagulase-negative staphylococci 20e39%
Enterobacteriaceae 14e27%
Anaerobes 16%
Streptococci 11%
574 M. Depypere et al. / Clinical Microbiology and Infection 26 (2020) 572e578
Table 2
Diagnostic criteria for fracture-related infection
Confirmatory criteria
Clinical signs
Sinus tract
Wound breakdown
Purulent drainage or the presence of pus
Microbiology
Phenotypically indistinguishable pathogens identified
by culture from at least 2 separate deep tissue/implant specimens
Histopathology
Presence of microorganisms in deep tissue specimens,
confirmed by using specific staining techniques for bacteria and fungi
Presence of >5 PMNs/HPF in chronic/late-onset cases
(e.g. fracture nonunion)
ESR, erythrocyte sedimentation rate; WBC, white blood cell count; CRP, C-reactive protein; PMNs, polymorphonuclear neutrophils; HPF, high-power field.
period in time should increase suspicion of FRI [7]. Although
studies focusing on patients with an acute/early FRI are currently
lacking, the diagnostic accuracy of serum inflammatory markers
(i.e. C-reactive protein, erythrocyte sedimentation rate, leucocyte
counts) in chronic/late-onset FRI was reviewed by van den Kie-
boom et al. [34]. Individual serum inflammatory markers are only
suggestive, but not confirmative of FRI [7,34].
Imaging
The most commonly used imaging modalities are conventional
radiography (i.e. X-ray), computed tomography (CT), magnetic
imaging resonance (MRI), three-phase bone scan (BS), fluo-
rodeoxyglucose positron emission tomography (FDG-PET) and
white blood cell (WBC) or antigranulocyte antibody (AGA) scin-
tigraphy [32]. In a systematic review, Govaert et al. [35] analysed
the accuracy of these imaging techniques for the diagnosis of FRI.
The review included seven studies on nuclear imaging techniques,
two on MRI and one on CT. Studies regarding conventional radi-
ography could not be identified. Although most data are available
on nuclear imaging, conventional radiography is generally per-
formed first when FRI is suspected. Suggestive radiological signs of
infection are implant loosening, bone lysis, failure of progression of
bone healing (i.e. non-union), sequestration and periosteal bone
formation [7]. Despite a high diagnostic accuracy, nuclear imaging
is still not a conclusive test to establish the presence of FRI, and is
therefore categorized as suggestive in the consensus definition
[32].
The imaging modality of choice depends on local availability, the
clinical questions, and experience with each technique of the
medical specialists involved [32].
Microbiology
Positive cultures of an identical pathogen from at least two
separate deep tissue/implant specimens is considered a confirma-
tory criterion of FRI (Table 2) [7,32]. Furthermore, in case of highly
virulent pathogens (e.g. Staphylococcus aureus, Escherichia coli, b-
haemolytic streptococci) one positive sample should raise a high
suspicion of infection [7,36].
Swab cultures have a low sensitivity and a high risk for
contamination. Therefore, tissue cultures should be preferred
[5,37,38]. Homogenization is considered as preferred method for
processing tissue samples. Methods to facilitate biofilm disruption
include vortexing, sonication or beadmill processing [36,39]. Son-
ication detaches biofilm-encased bacteria from the implant [39,40].
Onsea et al. [41] published a systematic review on tissue and son-
ication fluid sampling for the diagnosis of FRI [42]. The authors
Suggestive criteria
Clinical signs
Local/systemic (e.g. local redness, swelling, fever)
New-onset joint effusion
Persistent, increasing or new-onset wound drainage
Laboratory signs
Increased serum inflammatory markers (ESR, WBC, CRP)
Radiological and/or nuclear imaging signs
Microbiology
Pathogenic microorganism identified from a single deep tissue/implant specimen
concluded that, although sonication fluid culture is not superior to
tissue culture in the diagnosis of FRI, it may be a useful adjunct,
alongside conventional cultures, especially in antibiotic-pretreated
patients [41]. A recent study by Dudareva et al. [40] reported that
tissue cultures are more sensitive, and may be more specific, than
sonication for the diagnosis of orthopaedic device-related in-
fections. Although sonication seems to be a useful adjunct to con-
ventional tissue culture and is therefore included in the recently
published consensus definition, its added value in FRI still needs to
be established [32,41].
As organisms can exist in slow growth mode and small
numbers, enrichment broth cultures are helpful [43]. Enrichment
broths can be sub-cultured when cloudy or after a defined period of
time. This can take up to 14 days for detection of slow-growing
pathogens (e.g. Cutibacterium acnes) [44,45].
Localized growth and low numbers of organisms can lead to
sampling errors and an inevitable proportion of culture-negative
specimens [46]. Therefore, current recommendations state that
preferably five or more deep tissue samples should be taken
intraoperatively with separate instruments, from sites around the
fracture and adjacent to implants [32,46]. Moreover, tissue speci-
mens show the greatest accuracy when inoculated in blood culture
bottles [47,48]. Bacterial culture of sinus tracts is not recommended
as contamination with commensal skin flora is common [12,32].
To avoid false-negative culture results, antimicrobial therapy
should be stopped at least 2 weeks before sampling [42,46]. In
addition, antibiotics should be administered immediately after
sampling in suspected infection. In cases where there is implan-
tation of a new device, PJI data show that administering antibiotics
at the start of the procedure does not compromise culture results
and could protect the newly implanted device [49].
Histopathology
Studies focusing on histopathology in FRI are limited. A patho-
gnomonic sign for infection is the presence of microorganisms in
deep tissue taken during an operative intervention, as confirmed by
histopathological examination using specific staining techniques
(e.g. Grocott methenamine silver stain for invasive fungal in-
fections) [7].
The diagnostic value of the presence of polymorphonuclear
neutrophils (PMNs) in tissue biopsies is less clear. In the systematic
review by Onsea et al. [41], only three studies on histopathology
were identified. Recently, however, a study on the value of quan-
titative histopathology for the diagnosis of chronic/late-onset FRI
(i.e. unhealed fractures, more than 2 months from injury) has been
published [50]. In this study, a novel bimodal approach was used to
confirm or exclude infection. The complete absence of PMNs had a
 M. Depypere et al. / Clinical Microbiology and Infection 26 (2020) 572e578 575

high correlation with aseptic non-union (specificity 98%, positive
predictive value 98%). On the other hand, the presence of >5 PMN/
high power field (HPF) was associated with FRI (specificity 100%,
positive predictive value 100%). Therefore, the presence of neu-
trophils in biopsy samples (>5 PMNs/HPF) was included in the FRI
consensus definition as a confirmatory criterion [32].
Polymerase chain reaction
Scientific data on molecular techniques, such as PCR, in the field
of FRI are scarce [41]. These tests are rapid diagnostic techniques
that can detect viable and non-viable microorganisms. However,
the high sensitivity of PCR comes along with the risk of false-
positive results from contaminants [51].
Currently, new molecular technologies are being used for the
diagnosis of PJI. Next-generation sequencing (NGS), for example, is
capable of sequencing all DNA present in a given sample, resulting
in a more complete picture of the microbial genomes present and
has been proven useful in the identification of causative organisms
in culture-negative PJI [52,53]. NGS also often shows the presence
of multiple organisms that were missed with regular tissue culture,
questioning the reliability of conventional culture methods [52].
But this has not been specifically applied to FRI at the present time.
Treatment
General concepts
Successful management of FRI includes fracture consolidation,
restoration of the soft tissue envelope, return to function, preven-
tion of residual chronic infection and eradication of infection [5]. As
fracture fixation devices can be removed without loss of function
after osseous healing, suppressive therapy can bridge the time to
bone consolidation and removal of the internal fixation device [5].
Surgical aspects
Surgical management of FRI is based on two main concepts. The
first consists of debridement, antimicrobial therapy and implant
retention (DAIR). The second consists of debridement, implant
removaldin case the fracture has healeddor exchange, combined
with antimicrobial therapy. Fig. 1 shows a treatment algorithm
describing the basic treatment principles for FRI. As shown in Fig. 1,
the choice for implant retention or exchange depends on multiple
factors, one of them being the ability to perform a proper
debridement (e.g. considering implant type). This is illustrated by
the fact that the rate of treatment failure in case of DAIR is higher in
the presence of an intramedullary nail than plate osteosynthesis
[54]. This can be explained by the fact that the intramedullary canal
cannot be debrided in the presence of an implant.
The cornerstone of every surgical approach is a judicious and
well-planned debridement with removal of all dead tissues and
acquisition of deep tissue biopsies for microbiology and histopa-
thology. This is followed by osseous stabilization (if required) with
implant retention, exchange or external fixation, dead space man-
agement, delivery of antimicrobial therapy using local and systemic
antimicrobials and sufficient vital soft tissue coverage [55].
Fracture stability is crucial for bone consolidation and eradication
of infection. Although the presence of a foreign body increases the
risk of infection up to 100 000-fold [56], experimentally contami-
nated fractures without internal fixation have been shown to be
more prone to infection than similar fractures treated with internal
fixation [57,58]. Indeed, the advantage of implants for stabilization
outweighs their increased susceptibility to infection [59].
A major area of discussion remains the time point after which a
DAIR procedure in FRI is no longer advisable. Various clinical
studies reported excellent results with success rates of 90% and
more for implant retention in acute/early onset FRIs, occurring
within 3 weeks after fracture fixation [11,60]. In FRIs manifesting up
to 6 weeks after osteosynthesis, DAIR could achieve success rates of
around 70% [54,61]. If a DAIR is applied more than 10 weeks after
fracture fixation the success rate decreases to 51e67% [11,62]. These
studies implicate a continuum with declining success rate rather
than a clear cut-off. The treating multidisciplinary team has to be
aware of the biological process of maturing biofilm and therefore
declining success rate of implant retention as time elapses post
fracture fixation. Data show that antibiotics will not be able to
eradicate an infection after a certain age of biofilmdno matter how

Fig. 1. Algorithm describing the basic treatment principles for fracture-related infection (FRI). 1Preconditions for implant retention are: a stable osteosynthetic construct, a vital soft
tissue envelope, the ability to perform a proper debridement (considering implant type and the presence of necrotic tissues) and the time interval between fracture fixation and FRI
manifestation. Other factors influencing the decision process are the anatomical localization of the fracture (i.e. articular) and the host physiology [5]. 2Implant exchange in one or
two (multiple) stages. 3Difficult-to-treat infection: no biofilm-active antibiotic available while implant in situ; due to antibiotic resistance of the pathogen, drug intolerance of the
patient or incompatible drug-interactions. 4Eradication therapy: 12 weeks of antimicrobial therapy. Data from periprosthetic joint infections, no exclusive data for FRIs. 5Suppressive
antibiotic therapy until implant is removed. 6Osteomyelitis treatment: 6 weeks of antimicrobial therapy.
576 M. Depypere et al. / Clinical Microbiology and Infection 26 (2020) 572e578
long one treats with antibiotics [5,14]. Thusdaccording to the
current conceptdage of a biofilm/infection changes the surgical
approach (partial removal of the biofilm in case of DAIR, complete
removal in case of implant exchange) but not the duration of
antibiotic treatment. Nevertheless, future studies will be necessary
to improve understanding and optimize and individualize the
duration of antibiotic treatment.
Local application of antimicrobials at the site of infection
through different carriers has gained increasing attention [5].
Especially in the light of impaired blood flow to the site of infection
and necrotic bone tissue, the advantage of achieving very high local
concentration of antimicrobials with low systemic exposure is
compelling [5,63]. Furthermore, after an extensive debridement
they can be an important treatment option for ‘dead-space man-
agement’. In clinical practice, gentamicin, tobramycin, vancomycin,
and clindamycin are the most commonly available commercial
formulations for local antibiotic delivery in case of prevention and
treatment of FRI. This is because they are industrially incorporated
into PMMA, collagen fleeces and other bone void fillers (i.e. ce-
ramics) that are readily available for clinical use [63]. For PMMA,
where the exothermic polymerization process can result in tem-
peratures exceeding 100
C, thermal stability is a key factor in
determining the suitability of an antibiotic for incorporation [64].
Moreover, any antimicrobial or carrier should be thermally stable at
body temperature for the duration of release [64]. A recent study
found that b-lactam antibiotics degrade quite rapidly at 37
C, while
excellent long-term stability was observed for aminoglycosides,
glycopeptides and fluoroquinolones [64].
Successful cure of FRI requires not only surgical debridement
and fracture consolidation, but also soft tissue management
including soft tissue reconstruction and revascularization, if
needed [65]. The objective of soft tissue coverage is to provide a
robust antimicrobial barrier that prevents further contamination of
the fracture site and a biological environment conductive to frac-
ture healing. Furthermore, it will improve antibiotic delivery by
improving vascularization. Current clinical data suggest that
optimal definitive soft tissue coverage should be achieved as soon
as possible, not only for the prevention of FRI [66], but also in case
of treatment [67]. There is no evidence to indicate that negative
cultures at the time of debridement improves long-term outcome
or decreases risk for persistent infection [68,69]. The type of flap,
albeit muscular or fasciocutaneous, local or free also remains
controversial. Overall, it appears that muscle, fasciocutaneous, free
and pedicled flaps have similar results [70].
Antimicrobial therapy
Empirical antibiotic therapy
After surgical debridement and sampling, empirical antibiotic
therapy should be started in case of high suspicion of infection. The
choice of empiric therapy depends on the local epidemiology of
microorganisms and individual risk factors of the patient (i.e. pre-
vious antibiotics, comorbidities, allergies, previous hospitalisations,
previous debridement at the same site, previously recovered
pathogens). As a rule, initial empiric therapy should include a lipo/
glycopeptide and an agent against GNB, thereafter it should be
adapted according to culturing results as soon as possible [55].
Targeted treatment strategies
The duration of targeted antibiotic therapy is not based on
comparative trials, but expert opinion. In case of implant retention,
a total treatment duration of 12 weeks is recommended, whereas
after implant removal, 6 weeks is considered as sufficient [5].
Duration of intravenous (IV) therapy is derived from the results
of the OVIVA trial [71]. In this study, 1054 adults were treated for
bone or joint infections, and randomly assigned within 7 days after
surgery to receive either IV or oral antibiotics to complete the first
6 weeks of therapy. Results showed non-inferiority of oral antibi-
otics [71,72]. Therefore, the current recommendation is that IV
therapy should be limited to 1e2 weeks, until the patient (e.g. soft
tissue) is stable and culture results are known.
As studies solely focusing on FRI are scarce, targeted antibiotic
treatment strategies are currently extrapolated from guidelines for
other implant-related infections (i.e. PJI). Rifampicin is the agent of
choice to treat biofilm in staphylococcal implant-related infections.
It should only be initiated after thorough debridement to diminish
the bacterial load and when wounds are dry to avoid superinfection
with resistant microorganisms [73e75]. Because of rapid emer-
gence of resistant microorganisms, rifampicin must be given with a
companion antibiotic [76,77]. The first choice for oral combination
therapy in staphylococcal infections is a fluoroquinolone. However,
monotherapy with ciprofloxacin or levofloxacin against staphylo-
cocci is also not recommended because of rapid emergence of
resistance and a high treatment failure rate [78e80]. Other anti-
staphylococcal drugs such as cotrimoxazole, minocycline or fusi-
dic acid can be combined with rifampicin, but they have been less
intensively studied [81]. Linezolid monotherapy appears inferior to
a combination of rifampicin and linezolid in animal models,
although evidence suggests reduced levels of linezolid in combi-
nation with rifampicin in vivo [82,83]. Further studies are needed
regarding combination therapy. We consider glycopeptide antibi-
otics (vancomycin/teicoplanin) as an option for methicillin-
resistant staphylococci for the initial intravenous therapy [84]. For
implant-related infection caused by Cutibacterium acnes, the role of
rifampicin is unclear. Although rifampicin was highly efficacious in
an animal infection model [85], its clinical value in Cutibacterium
infections is less clear, because of a lack of prospective, randomized,
controlled studies [45,86].
In case of streptococcal infection, IV benzyl penicillin is rec-
ommended, for enterococcal infections ampicillin is first choice.
Both should be given for one to two weeks followed by oral therapy
with amoxicillin. For ampicillin-resistant enterococci, vancomycin
or daptomycin are first choice antibiotics for the whole treatment
course [55].
Fluoroquinolones have excellent activity on GNB biofilms
[75,87]. They should only be started after debridement and when
the wounds are dry, because of selection of resistance to fluo-
roquinolones when bioburden is high [75,87]. Non-fermenters,
such as Pseudomonas aeruginosa, should be treated initially with
b-lactam antibiotics such as piperacillin/tazobactam, cefepime,
ceftazidime or a carbapenem, although they have inferior bacteri-
cidal activity as compared to fluoroquinolones [88]. There is some
in vitro evidence of a decrease in bacterial killing rate with a high
bacterial load, so the addition of an aminoglycoside for 2e5 days
can be considered [89].
Follow-up
Data regarding clinical and radiographical follow-up times are
currently lacking. In general, a follow-up of a minimum of
12 months after cessation of therapy is required. Furthermore, the
follow-up frequency depends on local preferences and policies and
on the extent of infection.
Summary and recommendations
FRI remains one of the most challenging complications in
musculoskeletal trauma surgery. Recently, efforts were made by
multiple scientific organizations to improve the diagnostic and
treatment strategies related to FRI. There is increasing evidence
 M. Depypere et al. / Clinical Microbiology and Infection 26 (2020) 572e578
that multidisciplinary teamwork and collaboration between
healthcare workers are essential to achieve these goals and to
improve patient outcome in FRI [1,90,91]. Although at present time,
the domain of FRI is getting more attention, future research is still
necessary to improve patient outcome.
Transparency declaration
The authors have no conflict of interest to declare. No external
funding was received for this review.
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