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Vol 8, No 5, September/October 2000
285
Infection occurring after internal
fixation of a fracture is a devastat-
ing complication and may be extra-
ordinarily difficult to treat. The
introduction of an implant allows
bacterial invasion and alters both
the local environment and the func-
tion of immunocompetent cells.
Additionally, the soft tissues sur-
rounding the fracture site and the
vascularity of the injured region
are compromised, leading to delays
in healing and deficits in the im-
mune response.
Although infection may occur
after any form of surgical treat-
ment, infections are more com-
mon in patients with high-energy
fractures (whether closed or open)
and in patients who are immuno-
compromised. Internal fixation
has generally been considered to
increase the risk of infection after
fracture,
1
and it is recognized that
many common species of bacteria
are capable of colonizing the sur-
face of metal implants.

2,3
Further-
more, metal implants themselves
Dr. Schmidt is Assistant Professor of
Orthopaedic Surgery, University of Minnesota
School of Medicine, Minneapolis. Dr.
Swiontkowski is Professor and Chairman,
Department of Orthopaedic Surgery,
University of Minnesota School of Medicine,
Minneapolis.
Reprint requests: Dr. Schmidt, Hennepin
County Medical Center, 701 Park Avenue,
Minneapolis, MN 55415.
Copyright 2000 by the American Academy of
Orthopaedic Surgeons.
Abstract
Infection complicating internal fixation of fractures is a serious complication that
is difficult to treat. Whenever metallic devices are implanted in vivo, successful
biointegration requires that host cells colonize the highly reactive implant sur-
face. Bacteria such as staphylococci can also become adherent to metallic or poly-
meric implants and will compete with host cells for colonization of the implant
surface. Once adherent, these bacteria form a biofilm and undergo phenotypic
changes that make them resistant to the normal host immune response as well as
to antibiotics. Furthermore, metallic implants themselves cause specific deficits
in the function of the local immune system that may render the host response to
infection inadequate. Any associated soft-tissue injury causes even greater
impairment of local immune function. Despite the potentially detrimental
impact of internal fixation, fracture stability is of paramount importance in
achieving fracture union and in preventing infection. It has been demonstrated
in animal models that contaminated fractures without internal fixation develop

clinical infection more commonly than similar fractures treated with internal fix-
ation at the time of colonization. Because of the potential for infection whenever
internal fixation is utilized, appropriate prophylactic antibiotic coverage for
staphylococci and Gram-negative organisms should be provided. Open wounds
and severely damaged soft tissues require aggressive management so that a
viable soft-tissue envelope is maintained around the implant. Host factors such
as smoking and malnourishment should be corrected. Early diagnosis and
aggressive treatment of implant-related infection with antibiotics, debridement,
and maintenance of stable internal fixation are essential to successful treatment.
J Am Acad Orthop Surg 2000;8:285-291
Pathophysiology of Infections After
Internal Fixation of Fractures
Andrew H. Schmidt, MD, and Marc F. Swiontkowski, MD
appear to modulate local immune
function. Therefore, eradication of
implant-associated infection may
appear to necessitate removal of
the implant.
4
However, in the
case of a fracture, the implant pro-
vides stability to the injured limb,
which in turn lessens the likeli-
hood of infection and is necessary
for optimal healing of the bone
and soft tissues.
5
In a study of
hamster osteotomies contaminated
with Staphylococcus aureus, the

infection rate decreased from 71%
to 38% when internal fixation was
added.
6
Thus, surgeons treating
implant-associated infections after
fracture surgery may be faced
with competing priorities—treat-
ing the infection (which may re-
quire removal of the implant) and
treating the fracture (which neces-
sitates retention of the implant).
Bacterial Colonization of
Implants
Bacterial colonization of ortho-
paedic implants is a necessary, but
not in itself sufficient, first step in
the development of implant-related
infection. To document rates of
asymptomatic bacterial coloniza-
tion, Moussa et al
3
cultured ortho-
paedic fracture implants at the time
of removal from 21 patients. The
patients were scheduled to undergo
elective implant removal because
of hardware prominence, mal-
union, or nonunion. Despite the
absence of clinical infection in the

patients, cultures from 50% of the
implants grew organisms. There-
fore, bacteria may colonize im-
plants without causing sepsis, and
other factors besides the mere pres-
ence of bacteria must underlie the
development of clinical infection.
Important variables that may
affect whether infection occurs in a
given case include the specific
organism, the type of material on the
surface of the implant (i.e., dense
versus porous), the configuration of
the implant (i.e., solid versus hol-
low), the timing of bacterial colo-
nization, and the general health of
the host. Melcher et al
7
studied
infection after intramedullary nail-
ing in a rabbit model and found
that infection rates were higher for
hollow slotted nails than for solid
nails, higher for stainless steel nails
than for pure titanium nails, and
higher when reaming had been per-
formed. Whether these factors are
of clinical importance in humans is
not known. Other factors that must
be considered include the formation

of a “biofilm” due to the adsorption
of proteins, sugars, and other
macromolecules onto the implant
surface; possible changes in the
material itself attributable to the
host or the bacteria; the effects of
the implant on the local environ-
ment; and the systemic effects of the
implant in the host.
4
Microbial Adherence
Many types of bacteria, includ-
ing most coagulase-negative Staph-
ylococcus species, demonstrate an
ability to adhere to surfaces, in-
cluding metal.
2,4
Bacterial adher-
ence is considered to be a major
factor contributing to the develop-
ment of implant-associated infec-
tions.
2,8,9
Adherent Staphylococcus
organisms are more resistant to
antibiotics than the same strains
grown in a nonadhered state.
The mechanisms of bacterial
adherence depend on a complex
interplay between the infecting

organism, the local milieu, and the
properties of the biomaterial sur-
face.
2,4
Bacterial adhesion proceeds
through two stages.
10
First, nonspe-
cific physicochemical forces result
in an initial, reversible attachment
of the bacterium to an available sur-
face. Many factors, including the
surface charge of the substrate and
the relative hydrophobicity of both
the bacterium and the substrate,
modulate this process. Differences
in these surface characteristics result
in the variation in affinity for bacterial
colonization among various metals.
Once the bacterium is attached to
the substrate, molecular reactions
between bacterial surface macro-
molecules and substrate surfaces
result in permanent adherence to
the surface. Fibronectin is a protein
that modulates surface adhesion of
eukaryotic cells and has been shown
to promote S aureus adhesion as
well.
Metal Implants and Surface

Reactions
Gristina
2
has characterized the
complex events that occur after im-
plantation of a biomaterial as “the
race for the surface.” This compli-
cated series of interactions is poorly
understood but is fundamental to
the problem of biomaterial-related
sepsis. In theory, a freshly implanted
device presents a highly reactive
surface destined for one of two
fates: bacterial adhesion and colo-
nization or tissue integration. If
eukaryotic host cells integrate them-
selves into the surface first, bacterial
colonization will be actively inhibited,
and the biomaterial will become
tissue-integrated. If bacterial cells
colonize the surface first, a so-called
microzone may be established that
is conducive to further bacterial
growth and inhibits any immune
response. A key feature of this pro-
cess is the formation of “slime,” a
mucopolysaccharide biofilm that
enhances bacterial nutrition, inter-
feres with phagocytosis, influences
antibody function, and promotes

further bacterial aggregation.
2
The production of one type of
this so-called slime, bacterial glyco-
calyx, is an important determinant
of antibiotic resistance. Gristina and
Costerton
8
reported that 76% of
implants retrieved from patients
with prosthesis-related infections
had causative bacteria enclosed in a
glycocalyx biofilm. The mature bio-
film consists of both the accumulated
bacterial mass and associated extra-
cellular glycocalyx. When infec-
tions about implants occur, bacterial
adherence may limit the usefulness
of cultures because infecting organ-
isms may be protected within the
biofilm.
Knowledge of the mechanisms
that promote bacterial adherence to
the surfaces of implants provides a
potential method to modulate this
phenomenon.
10
For instance, the
surface of titanium implants can be
modified by the covalent attach-

ment of an organic monolayer.
This may provide a method to de-
crease bacterial adherence, modify
bacterial behavior by attachment of
functional cell-surface receptors, or
provide antibiotics or immuno-
globulins to the surface of the im-
plant. Surface modification of im-
plants remains an area of active
research.
2,10
In addition, Gristina’s
theory highlights the importance of
decreasing the likelihood of bacter-
Infection After Internal Fixation of Fractures
Journal of the American Academy of Orthopaedic Surgeons
286
ial colonization by the use of pro-
phylactic antibiotics, atraumatic
surgical technique, and materials that
are designed to promote eukaryotic
cellular integration and inhibit the
formation of a biofilm.
Implant Characteristics
It is known that the rate of infec-
tion about a foreign body is related
to the material properties and
shape of the implant. For example,
infection rates are greater with
multifilament sutures than with

monofilament sutures of the same
material. With respect to ortho-
paedic implants, it has been shown
that infections are more likely after
intramedullary nailing with hollow
nails than with solid-core nails.
11
With respect to material types, it
has been shown that bacteria
adhere differently to different sub-
strates. The relative propensity of
Staphylococcus epidermidis to adhere
to a given material in vitro has
been directly related to rates of bac-
terial colonization and infection in
vivo.
9
In a study by Chang and
Merritt,
9
bacterial adherence to
stainless steel was greater than that
to polymethylmethacrylate and
titanium, which is significant given
that most fracture fixation devices
are manufactured from stainless
steel. Using a rabbit model, Arens
et al
12
showed that the infection

rate in a wound contaminated with
S aureus was 75% with stainless
steel plates, compared with 35%
with titanium plates.
The surface characteristics of the
implant are important in determin-
ing the degree of bacterial adher-
ence; the resultant effect may be dif-
ferent for acute infections and
delayed infections. Dense materials
promote fibrous encapsulation and
generally provoke minimal tissue
reaction.
13
Porous materials allow
ingrowth of the surrounding tissue
into their pores. In an animal
model, Merritt et al
13
found that in-
oculation of bacteria at the time of
implantation favored infection in
porous material, whereas late inocu-
lation favored infection in dense
material. Once fibrous ingrowth
occurred about a porous implant,
late infection was less likely than it
was about a dense implant. The clin-
ical implication is that porous im-
plants may present a greater risk of

infection in a contaminated wound.
However, in a sterile wound, where
there is little risk of immediate bac-
terial contamination, use of porous
devices may protect against delayed
hematogenous infection. In another
study, it was found that the dose of
S aureus necessary to infect cobalt-
chrome implants with polished sur-
faces was 40 times greater than the
dose needed to infect implants with
porous surfaces.
14
Titanium im-
plants were less susceptible to infec-
tion but demonstrated the same
effect.
These differences in the propen-
sity for infection can be explained
by the fact that implant material,
shape, and size are all factors that
affect the nature of the reactive sur-
face available for bacterial adher-
ence. Both the material itself and
its surface characteristics appear to
be important determinants of the
frequency of infectious complica-
tions. Although titanium implants
may be less susceptible to infection
in animal studies, this has not been

proved in humans.
Immunomodulation by
Metal Implants
Up to 13% of the population is sen-
sitive to nickel, cobalt, or chromi-
um.
15
Other metals, including tita-
nium, aluminum, and vanadium,
may also cause hypersensitivity
reactions in susceptible persons.
The manifestations of metal sensi-
tivity are subtle and may alter the
host response to the implant and
affect local immune function. In a
hamster model, immunization with
nickel chloride for 5 weeks protected
against infection about stainless
steel pellets, whereas immuniza-
tion for 10 weeks increased the
infection rate.
16
In patients with
total joint implants or dynamic hip
screws, metal is found in local and
distant lymph nodes, bone mar-
row, liver, and spleen. Morpho-
logic changes occur within the
lymph nodes, suggesting that im-
mune function has been altered.

Furthermore, changes in cytokine
levels are found in patients with
total joint replacements.
Widespread alterations of im-
munologic function are seen in re-
sponse to metal implants. During
the first few days after implantation,
the specific cellular content of the
inflammatory response varies de-
pending on the material used.
16
Direct contact between the inflam-
matory cells and the biofilm, as well
as interactions promoted by metal
ions, surface macromolecules, and
free radicals present at the reactive
metal surface, all influence the func-
tion of these cells. Inhibition of T-
cell activation, impairment of poly-
morphonuclear leukocyte super-
oxide production, and plasma-cell
activation have all been reported.
17-19
In addition, biomaterials have been
shown to influence chemotaxis and
complement activation.
20
Although the precise meaning of
these findings is unclear, alteration
of the immune response is a defi-

nite consequence of use of metallic
implants. This may be of clinical
importance, especially in patients
with preexisting immunodeficiency
or malnutrition. It is possible that
these interactions could be harm-
ful, promoting infection in some
situations; in other circumstances,
however, the very same effects
might make the wound less suscep-
tible to bacterial invasion. Much
more research is necessary to fur-
ther define these interactions and
to delineate the ways that biomate-
rials might enhance immune sys-
Andrew H. Schmidt, MD, and Marc F. Swiontkowski, MD
Vol 8, No 5, September/October 2000
287
tem function rather than limit its
effectiveness.
Clinical assessment of the general
health of the patient, including im-
mune function and nutritional sta-
tus, is prudent if an implant-related
infection is suspected. Specifically,
patients should be asked whether
they smoke, have received an allo-
geneic blood transfusion, have a
known immunodeficiency syn-
drome, or have had possible expo-

sure to the human immunodefi-
ciency virus. Laboratory evidence
of malnutrition includes a total
lymphocyte count of fewer than
1,500 cells per cubic millimeter and
a serum albumin concentration of
less than 3.5 g/dL.
The Role of Fracture
Stability in Infection
Although it is known that the pres-
ence of a foreign body increases the
risk of infection, clinical experience
suggests that internal fixation of
open fractures reduces the infec-
tion rate. It is postulated that inter-
nal fixation reduces the amount of
soft-tissue damage caused by bone
fragments, thereby making the
wound a less hospitable environ-
ment for bacterial growth.
6
In one study involving a hamster
model,
6
71% of femoral osteotomies
inoculated with S aureus organisms
were culture-positive after 2 weeks.
When the osteotomy was stabilized
with 0.9-mm Kirschner wires, only
38% of the animals had positive cul-

tures. However, when the osteotomy
was contaminated with the Gram-
negative organism Proteus mirabilis,
the incidence of positive cultures
was increased by internal fixation
(57% vs 40%). Clinical infection was
not evident in the adjacent soft tis-
sues, which may reflect the greater
propensity for P mirabilis to survive
on the implant owing to its biofilm.
In another study involving a
rabbit model, tibial fractures were
stabilized with either a dynamic
compression plate (stable group) or
a loose intramedullary rod (unsta-
ble group) and inoculated with S
aureus.
21
The infection rate was
double in the unstable group (71%
vs 35%).
It is not known for certain why
stable fractures are less susceptible
to infection. Perhaps unstable frac-
tures result in greater damage to
surrounding tissues, thereby pro-
moting inflammation and local
immunosuppression. In contrast,
stable soft tissues may promote
more rapid vascularization.

Prevention of Infections
After Internal Fixation of
Fractures
Given the difficulty and increased
expense of the treatment of infec-
tion after internal fixation of frac-
tures,
22
prevention is extremely im-
portant. There are two essential
steps in the prevention of infection:
early administration of intravenous
(IV) antibiotics and proper surgical
management of fractures.
Prophylactic Antibiotic Therapy
Antimicrobial prophylaxis is a
necessary adjunct to the manage-
ment of fractures that require sur-
gery. In cases of closed fracture,
administration of a first-generation
cephalosporin 30 minutes before
surgery provides adequate cover-
age. It is not necessary to continue
prophylaxis for more than 24
hours.
23
Application of the bacteriostatic
compound sulfanilamide to pre-
vent infection in open fractures
was first reported in 1939 and rep-

resents one of the earliest success-
ful examples of antibiotic prophy-
laxis. Since then, the management
of open fractures has advanced
considerably. For open fractures
that are contaminated by bacteria
at the time of injury, early adminis-
tration of parenteral antibiotics has
been shown to reduce the infection
rate.
24
The specific agent adminis-
tered is chosen empirically on the
basis of the severity of the injury
and the type of contamination ex-
pected (Table 1). For Gustilo grade
I and grade II fractures, a first-
generation cephalosporin is given.
For grade III injuries, an aminogly-
coside is added, or a third-genera-
tion cephalosporin is used. Penicil-
lin must be administered if the
wound has been contaminated by
soil. Tetanus prophylaxis should
be given to any patient who has not
had documented tetanus vaccina-
tion. When combined with early and
aggressive surgical debridement, it
is not necessary to continue pro-
phylactic antibiotics for more than

24 hours.
The organisms that are typically
cultured from infected fracture sites
are Gram-positive (usually staphy-
lococci) and nosocomial Gram-
negative bacteria. Wound cultures
are of little benefit except in unusu-
al circumstances, such as a marine
injury. Although cultures are of
limited value in predicting infect-
ing organisms, the final postde-
bridement culture has the highest
correlation with the development
of infection.
25
Recently, the antibiotic bead-
pouch technique has been recom-
mended for use in more severe
open fractures.
26
This involves
placing polymethylmethacrylate
beads impregnated with a heat-
stable antibiotic into the wound
and covering the wound with an
occlusive bandage. The beads are
made by hand or with a mold and
are placed on 18-gauge surgical
wire or a heavy nonabsorbable
suture. Either tobramycin (2.4 to

4.8 g per batch of cement) or van-
comycin (1 to 2 g per batch of ce-
ment) is used. In a comparative
study, this technique resulted in a
decrease in infection rate from 16%
to 4% in patients with severe open
Infection After Internal Fixation of Fractures
Journal of the American Academy of Orthopaedic Surgeons
288
tibial fractures treated with intra-
medullary nailing.
27
Surgical Technique
Given that rapid soft-tissue inte-
gration with the implant and a
healthy vascular supply are of key
importance in limiting the ability of
bacteria to win “the race for the
surface,” the importance of atrau-
matic surgical technique when
operating on fractures becomes
obvious. Minimizing the surface
area of exposed bone and of im-
plants will lessen the likelihood of
infection, because the area avail-
able for bacterial adherence will be
smaller. Furthermore, one should
ensure that healthy tissue is pres-
ent adjacent to the implant and
bone, so that viable host cells are

available to cover the surface im-
mediately.
When operating on closed frac-
tures, it is of paramount impor-
tance to limit the degree of bone
devascularization and to cover
any implants with healthy soft tis-
sue. Skin must be examined for
areas of contusion or necrosis.
Muscle viability is assessed on the
basis of its color, capacity to bleed,
and contractility. During exposure,
skin edges should not be crushed
or retracted under tension, and
devitalized muscle should be re-
moved. Sutures may be used to
retract tissues, rather than forceps
or hand-held retractors, which may
further crush tissues. Periosteal
stripping is generally not per-
formed, and bone fragments are
not further devascularized. Frac-
ture reduction should be done
when possible by using principles
of ligamentotaxis, rather than
direct reduction with unnecessary
exposure of the bone. Open re-
duction and fixation of articular
injuries is best delayed until the
soft-tissue envelope is healthy.

Open fractures generally have
more severe soft-tissue injury, as
well as bacterial contamination.
An open wound may be consid-
ered infected if more than 8 hours
elapsed after injury before treat-
ment was initiated. Open fractures
require immediate aggressive de-
bridement, fracture stabilization,
and early reconstruction of the soft
tissues. The edges of the traumatic
wound should be excised, along
with any other devitalized skin and
muscle. The entire zone of injury
requires assessment for nonviable
tissue and contamination. All ne-
crotic and foreign material should
be removed.
Generally, some form of irriga-
tion solution is used, but the role of
antibiotic solution and the efficacy
of high-pressure lavage are current-
ly controversial. It has been shown
that solutions containing antibiotic
are no better at removing bacteria
than plain saline. Detergents, such
as castile soap and benzalkonium
chloride, have shown promise in
removing bacteria. There is evi-
dence that the efficacy of these irri-

gation solutions may vary with the
type of bacterium, with soap more
effective for Pseudomonas aeruginosa
organisms and benzalkonium chlo-
ride more effective for S aureus.
28
Current recommendations are to
use sequential irrigation with sa-
line, then soap, and finally benzal-
konium chloride.
High-pressure pulsatile lavage
was developed to provide an effi-
cient means of mechanical debride-
ment. However, recent evidence
suggests that high-pressure lavage
contributes to further devascular-
ization of the fracture edges.
29
One
recent study showed that high-
pressure lavage was of no benefit in
removing bacteria from fresh frac-
tures (those treated within 3 hours
of injury).
29
For fractures first seen
after 6 hours, bacterial adherence
was more pronounced, and high-
pressure lavage was needed to ster-
ilize the implant. It seems prudent

to use high-volume irrigation at a
low pressure, except for fractures
seen after a delay and those that are
grossly contaminated.
Regardless of whether one is
treating open or closed injuries,
fracture implants should never be
left exposed. The use of a bead
Andrew H. Schmidt, MD, and Marc F. Swiontkowski, MD
Vol 8, No 5, September/October 2000
289
Table 1
Choice of Antibiotic Therapy for Closed and Open Fractures
Fracture Type Recommended Antibiotic
Closed First-generation cephalosporin (cefazolin, 2 g IV
loading dose, 1 g IV every 8 hours for 3 doses)
Grade I and II open First-generation cephalosporin (Ancef, 2 g IV
loading dose, 1 g IV every 8 hours for 3 doses)
Grade III open Third-generation cephalosporin (ticarcillin-
clavulanate, 3.1 g IV every 8 hours) or first-
generation cephalosporin plus aminoglycoside
(gentamicin or tobramycin)
All open fractures Add penicillin for injuries contaminated by soil.
Add tetanus prophylaxis if history of tetanus
immunization is not known. Discontinue
antibiotics after 24 hours; start again for any
major procedure (e.g., internal fixation,
bone grafting, muscle flap).
pouch is an effective way to manage
dead space and to sterilize open

wounds. This may be done by fash-
ioning tobramycin-impregnated
methylmethacrylate beads (con-
taining 2.4 to 4.8 g of tobramycin
per package of cement), placing
them into the wound, and then
sealing the wound with an occlu-
sive, impermeable dressing.
In general, wound debridement
should be repeated every 48 hours.
Definitive soft-tissue closure or
reconstruction should be per-
formed within the first week when
possible.
Summary
Implant-associated infections pre-
sent a formidable challenge to the
orthopaedic surgeon. Tissue dam-
age related to the initial injury is
potentiated by the adverse biologic
effects of internal fixation devices,
which further decrease vascularity,
suppress the function of local im-
munocompetent cells, and provide
a site for bacterial adherence.
Knowledge of the pathophysiol-
ogy of implant-related infections
leads to a logical approach for man-
agement. Skeletal stability must be
maintained, for, as McNeur

30
has
stated, “there is only one thing
worse than a stable infected frac-
ture and that is an unstable infected
fracture.” As for other types of
wound infection, antibiotic therapy
and debridement are the corner-
stones of treatment. In acute infec-
tions with favorable soft tissues, the
implant may be successfully re-
tained as long as fracture union
seems to be progressing favorably.
In chronic infections, exchange or
removal of the implant may be nec-
essary, along with soft-tissue and
skeletal reconstruction.
Infection After Internal Fixation of Fractures
Journal of the American Academy of Orthopaedic Surgeons
290
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Andrew H. Schmidt, MD, and Marc F. Swiontkowski, MD
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