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32
limited wound exploration followed by primary
closure of the wound was performed. The patient
was repatriated on day nine by airplane to our
hospital. An extended wound revision with
debridement, removal of multiple foreign bodies
(small stones, grass) and synovectomy of the
knee joint and lavage was performed (Fig.4.2),
followed by negative wound pressure therapy.
Intravenous antibiotic therapy according to the
resistance pattern of the isolated bacterial species
was administered. Multiple intraoperative swabs
and soft tissue probes showed cultures of
Enterobacter cloacae, Enterococcus species and
Corynebacterium species. Two weeks later, a
denitive osteosynthesis of the patella (Fig. 4.3)
with tension wire was performed, associated with
a negative pressure wound therapy with instillation technique using polyhexanide solution
(0.04%) was performed (Fig. 4.4). Four days after
the Instillation technique, wound swabs became
sterile. Seven days after the tension wire osteosynthesis, the wound was closed by secondary intention with uneventful healing (Fig.4.5). Removal
of the hardware after consolidation of the patella
fracture was done 5months later (Fig.4.6) in com-
F. Ziegenhain and G. N. Jukema
Fig. 4.3 Tension wire osteosynthesis of the patella
Fig. 4.4 Negative Pressure Instillation Technique (note
the double tubing: a suction and a smaller sized instillation tube) with polyvinylalcohol (white foam) and polyurethane foam (black foam)
Fig. 4.2 Intraoperative situs of the open knee joint:
severe infection of the joint with granulation tissue
Fig. 4.5 Soft tissues 4months after trauma
4 Aetiology andPathogenesis: Causative Agents
33
Fig. 4.6 Radiological outcome (CT) 1year after trauma
bination with an arthrolysis of the knee joint. Now,
2.5 years after the accident, the patient is doing
well with a wide range of motion of the knee joint
(Flexion 130 degrees, full extension) without any
signs of infection (Figs.4.7 and 4.8).
4.2.1 Summary
Soft tissue and bone infections in orthopaedic
and trauma surgery have a high risk for recurrence, especially if osteosynthesis hardware like
plates, intramedullary nails and prosthesis are in
situ. For that reason, from the very beginning, the
care for soft tissues should have the highest priority to reduce the risk of an infection in emergency
trauma situations, which can end up in chronic
bone and joint infections. In case of closed fractures with soft tissue injury and even more in primary open fractures, from the very rst start
fracture treatment should be brought in line with
the soft tissue damage (‘do not further harm’).
The experience of the orthopaedic and trauma
surgeon plays an important role in the timing of
the following procedures, aiming to reduce the
risk of infection.
Debridement and lavage of soft tissue injuries
are still the corner stone for future care, but mod-
Fig. 4.7 Soft tissues of the knee joint after 15months
Fig. 4.8 Clinical outcome after 15months
ern wound treatment concepts like negative pressure wound pressure therapy with installation
technique of polyhexanide solution, can guide us
to an improved outcome for patients in combination with a shorter hospital stay and reduced number of operative procedures needed for patient’s
recovery and nally to achieve a better outcome.
34
F. Ziegenhain and G. N. Jukema
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Bacterial Resistance
MarcoTrevenzoli, VincenzoScaglione,
andAnnamariaCattelan
5
5.1 Introduction
Penicillin, the initial antibiotic employed historically, demonstrated remarkable efcacy in treating bacterial infections among soldiers during
World War II.However, penicillin-resistant bacteria emerged just a few years later. In response,
new antibiotics were developed, but bacteria
quickly evolved resistance to these as well. By
the 1980s, the discovery of new antibiotics had
slowed to a crawl. As a result, bacterial infections
caused by multidrug-resistant or extensively
drug-resistant pathogens are now a major global
health threat [1].
Antimicrobial resistance (AMR) occurs when
microorganisms change their susceptibility to
antimicrobial pattern over time, resulting in no
longer responding to antibiotics, making infec-
M. Trevenzoli · V. Scaglione
Infectious and Tropical Diseases Unit, Department of
Medicine-DIMED, Padua University Hospital,
Padova, Italy
e-mail: marco.trevenzoli@aopd.veneto.it;
vincenzo.scaglione@aopd.veneto.it
A. Cattelan (*)
Infectious and Tropical Diseases Unit, Department of
Medicine-DIMED, Padua University Hospital,
Padova, Italy
Department of Molecular Medicine-DMM,
University of Padua School of Medicine,
Padova, Italy
e-mail: annamaria.cattelan@unipd.it
tions harder to treat and increasing the risk of disease spreading, severe illness, and death.
In Europe, more than 670,000 infections occur
every year, and 33,000 people die due to bacteria
resistant to antibiotics, with billions of Euros in
cost for healthcare systems [2].
Several factors are linked to AMR:
• The overuse and misuse of antimicrobials in
humans and animals.
• The spread of antibiotic-resistant bacteria
through healthcare settings.
• The emergence of new antibiotic resistance
genes.
Antibiotic therapy may be considered a
double- edged sword. On one hand, from the ecological impact, the best antimicrobial molecule is
not the one given. On the other hand, antimicrobial therapy saves lives.
Several bacteria have been highlighted in
recent years for the AMR issue [3]:
Methicillin-resistant Staphylococcus aureus
(MRSA).
Vancomycin-resistant Enterococcus (VRE).
Carbapenem-resistant Enterobacterales (CRE).
Multidrug-resistant Pseudomonas aeruginosa
(MDR PA).
Carbapenem-resistant Acinetobacter baumannii
(CRAB).
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2025
P. Ruggieri et al. (eds.), Bone and Joint Infections, https://doi.org/10.1007/978-3-031-96383-4_5
37
38
M. Trevenzoli et al.
In addition, in bone and joint infections (BJIs),
the complex anatomy of bones and joints can
make it difcult for antibiotics to reach the site of
infection.
Several measures can be implemented to
reduce the risk of AMR, including: (i) antimicrobial stewardship (AS) programs in order to maximize clinical outcome avoiding unnecessary and
ecological collateral damage due to antimicrobials [4]; (ii) practicing hand hygiene, both in and
out of healthcare settings [5, 6]; (iii) vaccination
campaigns for relevant contagious diseases [7];
(iv) development of new antibiotics and other
treatments for infections [8].
5.2 Antimicrobial Resistance:
Innate, Acquired,
andAdaptive
• Innate resistance is the natural ability of a bac-
terium to resist an antibiotic. For example, all
Gram-negative bacteria have an outer mem-
brane that makes them resistant to many anti-
biotics such as glycopeptides.
• Acquired resistance develops when a bacte-
rium gains the ability to resist an antibiotic to
which it was previously sensitive. This can
happen through mutation or horizontal gene
transfer.
• Adaptive resistance is a temporary state of
resistance that a bacterium can develop in
response to exposure to an antibiotic. It is
thought to be caused by changes in gene
expression [9–11].
Horizontal gene transfer is the most typical
way that bacteria acquire resistance genes. It can
arise through three main mechanisms:
• Transformation: bacteria take up free DNA
from the surrounding environment.
• Transduction: This is a process in which a
bacteriophage, which is a virus that infects
bacteria, transfers DNA from one bacterium to
another.
• Conjugation: This is a process in which two
bacteria exchange DNA directly [1].
5.3 Mechanisms ofAntibiotic
Resistance
Antibiotic resistance is typically caused by the
destruction or modication of antibiotics,
changes to the targets that antibiotics attack, or
reduced accumulation of antibiotics in bacterial
cells. This can happen through reduced permeability of the cell wall or increased efux of antibiotics from the cell. Alternatively, antibiotic
resistance can be the result of a global adaptation
of the entire bacterial cell [1].
The following text describes the principal
resistance mechanisms associated with the most
frequently used antibiotics for the pathogens
commonly encountered in clinical practice.
5.3.1 Antibiotic Destruction
The production of beta-lactamase enzymes,
which break down beta-lactam antibiotics, is a
major cause of penicillin resistance.
In 1940, the rst β-lactamases were described
[12], a year before penicillin entered clinical
practice. Over 1000 β-lactamases since then has
been reported from a variety of bacteria, and they
represent the most frequent resistance mechanism leading to Gram-negative bacteria β-lactam
resistance.
In the chromosome or in mobile genetic elements can be found genes encoding β-lactamases,
which have facilitated their transmission among
bacteria. In the 1960s, TEM-1, a plasmidencoded β-lactamase, was discovered in Gramnegative bacteria. Since then, the introduction of
new β-lactams has been followed by the identication of new β-lactamases that can break down
the new compound.
For example, in the early 1980s, the introduction of third-generation cephalosporins was
quickly followed by the identication of
plasmid- encoded β-lactamases in 1983 that
could possibly hydrolyze third-generation cephalosporins (Extended-Spectrum β-LactamasesESBLs) [13, 14].
Another beta-lactamase group of great clinical
importance in Gram-negative bacteria includes:
5 Bacterial Resistance
39
Carbapenemases: These enzymes are able to
hydrolyze carbapenems, which are the most
potent beta-lactam antibiotics. Carbapenemresistant bacteria are a major threat to public
health, as there are very few antibiotics that
are still effective against them.
Metallo-beta-lactamases (MBLs): MBLs are a
class of beta-lactamases that are resistant to
beta-lactamase inhibitors, such as clavulanic
acid and tazobactam. In addition, all of these
enzymes can efciently hydrolyze carbapenems, while only monobactams are uniformly
resistant to hydrolysis by these versatile
enzymes. Consequently, bacteria producing
metallo-beta-lactamases (MBLs) are challenging to treat, and their prevalence is steadily
increasing [15].
The emergence of new beta-lactamase groups
is a major challenge for public health. It is important to continue to develop new antibiotics and
new strategies to prevent the spread of betalactamase- producing bacteria.
5.3.2 Antibiotic Modication
The primary mechanism responsible for clinically signicant resistance to aminoglycosides
and chloramphenicol is the enzymatic modication of the antibiotic molecule.
Aminoglycoside-modifying enzymes (AMEs)
are a group of enzymes that can modify aminoglycoside antibiotics by adding various chemical
groups to them. This modication might reduce
the ability of the antibiotic to bind to its target
and makes it less effective. AMEs are encoded by
genes that are often located on mobile genetic
elements (MGEs), such as plasmids and transposons, allowing genes to be easily transferred
between different bacteria [16].
In parallel, chloramphenicol acetyltransferases (CATs) are a group of enzymes that can
acetylate chloramphenicol, which is a specic
type of antibiotic. Acetylation reduces the activity of chloramphenicol and makes it less effective
at killing bacteria. Much like AMEs, CAT genes
exhibit a propensity for residing on MGEs,
enabling facile inter-bacterial transfer and
thereby contributing to the widespread dissemination of antibiotic resistance. This intricate
interplay of enzymatic modications unveils the
complex molecular dynamics that underscore the
adaptability and persistence of antibiotic resistance mechanisms in bacterial populations [17].
5.3.3 Modications ofAntibioticActivating Enzymes
Nitrofurantoin is a prodrug that requires activation by bacterial reductases to become effective.
The two main nitroreductases involved in nitrofurantoin activation are NfsA and NfsB.Mutations
in the genes encoding these enzymes can lead to
nitrofurantoin resistance [18].
5.3.4 Target Replacement or Target Bypass
Methicillin resistance in Staphylococcus aureus
and the mechanism underlying β-lactam resistance in Streptococcus pneumoniae is a replacement of the bacterial penicillin-binding proteins
(PBPs).
Penicillin-binding proteins (PBPs) are
enzymes that are essential for cell wall synthesis
in bacteria. β-lactam antibiotics work by inhibiting PBPs, which prevents the bacteria from building a strong cell wall.
For Streptococcus pneumoniae, β-lactam
resistance can be caused by the replacement of
native PBP genes with mosaic PBP genes, which
are created by the recombination of foreign
DNA and native DNA from β-lactam-resistant
streptococci. This process is known as transformation [19].
For Staphylococcus aureus, methicillin resistance is caused by the acquisition of the mecA
gene. The mecA gene encodes a unique PBP
called PBP2a, which has a very low afnity for
all β-lactam antibiotics. This allows
Staphylococcus aureus to continue building a
strong cell wall even in the presence of β-lactam
antibiotics [20].
40
M. Trevenzoli et al.
Other examples of antibiotic resistance mediated by the replacement of bacterial targets
include:
Glycopeptide resistance in Enterococci:
Enterococci can acquire resistance to glyco-
peptide by replacing the glycopeptide target
(the terminal d-Alanine-d-Alanine moiety of
peptidoglycan precursors) with a different
molecule, reducing the binding afnity of the
antibiotic molecule [21].
Trimethoprim resistance in bacteria:
Trimethoprim inhibits dihydrofolate reductase
(DHFR), an enzyme involved in folate metab-
olism. Bacteria can become resistant to trime-
thoprim by acquiring genes that encode
trimethoprim-resistant DHFR enzymes.
Sulfonamide resistance in bacteria: Sulfonamides
inhibit dihydropteroate synthase (DHPS), an
enzyme involved in folate metabolism.
Bacteria can become resistant to sulfonamides
by acquiring genes that encode sulfonamide-
resistant DHPS enzymes [22].
main route of entry for hydrophilic antibiotics
into Gram- negative bacteria. They are small
proteins that form channels in the outer membrane. The type and the number of porins
expressed on the outer membrane could possibly affect the entry of hydrophilic antibiotics,
and, hence, the susceptibility of the bacterial
cell to them. Porin loss, conductance of modication of the size of porins, minimized
expression of porins, and changes in porin
expression, are all associated with resistance to
several molecules [27].
tance in Gram-negative bacteria:
• Penicillin resistance in Neisseria gonor-
• Cephalosporin resistance in Enterobacterales:
• Fluoroquinolone resistance in Pseudomonas
5.3.5 Target Site Alteration
Linezolid is an antibiotic that binds to the 23S
rRNA and inhibits protein synthesis. Mutations in
the 23S rRNA can prevent linezolid from binding,
determining resistance to linezolid. Other mechanisms of linezolid resistance include: mutations in
the ribosomal proteins L3 and L4; methylation of
the 23S rRNA by the cfr enzyme [21, 23]. Other
examples are mutations in genes encoding the
gyrase and/or topoisomerase IV enzymes which
represent the most common mechanism of quinolone resistance [24]. Rifampicin resistance is
mostly the result of mutations in the RNA polymerase beta subunit gene [25].
5.3.7 Eux Pumps
Bacterial efux pumps are molecular systems
that use energy to transport toxic molecules out
of the cell.
types:
1. Multidrug efux pumps: These pumps are
2. Substrate-specic efux pumps: these pumps
5.3.6 Decreased Permeability
oftheBacterial Outer
Membrane
A permeability barrier that can restrict the
entry of antibiotics is the outer membrane of
Gram- negative bacteria [26]. Porins are the
tance decreasing antibiotic concentration inside
the cell below the level needed to kill the bacteria
[27, 31].
Examples of porin-mediated antibiotic resis-
rhoeae: N. gonorrhoeae can develop penicillin resistance by reducing the expression of
the porin OmpC [28].
Enterobacterales can develop cephalosporin
resistance by reducing the expression of the
porins OmpF and OmpC [29].
aeruginosa: P. aeruginosa can develop uoroquinolone resistance by reducing the expression of the porins OprD and OprF [30].
Efux pumps can be classied into two main
typically chromosomally encoded and can
transport a wide range of antibiotics and other
compounds out of the cell.
are often located on MGEs and are specic for
a particular type of antibiotic or compound.
Efux pumps contribute to antibiotic resis-
5 Bacterial Resistance
41
5.4 Biolm
Biolms are a major challenge in healthcare, as
they can lead to persistent and difcult-to-treat
infections [32]. They are often found on medical
devices, such as implants and catheters, but can
also form on natural surfaces, such as teeth and
wounds, or dead bone.
Biolms are made up of a variety of microorganisms, including bacteria, fungi, and algae,
which are embedded in a sticky matrix of extracellular polysaccharides. This matrix provides
the microorganisms with protection from the outside environment, including antibiotics [33].
Biolms are also able to coordinate their
behavior. This allows them to share nutrients,
communicate with each other, resist antibiotics,
and develop new ways to evade the immune
system.
As a result of these factors, biolm infections
can be very hard to treat and, in several cases, the
only way to cure a biolm infection is to remove
the infected device or tissue [32, 33].
5.5 Steps inBiolm Formation
Genetic research reveals that biolm formation is
a multistep process that requires specialized cell
signalling (quorum sensing) and transcription of
a unique set of genes. Moreover, several factors
can inuence biolm formation, such as temperature, nutrient availability, and pH [34–36].
Biolms contain channels that separate microcolonies, and their mechanical stability is due to
the viscoelastic properties of the extracellular
polymeric substance (EPS) matrix.
Researchers have identied a few common
steps in biolm formation:
1. Initial attachment to the surface: Bacteria rst
attaches to a surface through a variety of
mechanisms, such as electrostatic interactions, van der Waals forces, and specic
adhesins.
2. Microcolony formation: Once attached, bac-
teria begin to multiply and form microcolonies. This process is mediated by quorum
sensing, a cell-to-cell communication system
that allows bacteria to coordinate their
behavior.
3. Maturation and architecture formation: The
biolm continues to mature and develop a
complex architecture. This process involves
the production of the EPS matrix, which
encases the bacteria and provides them with
protection.
4. Detachment and dispersion: Once mature, the
biolm can detach from the surface and disperse the bacteria to new locations. This process is also mediated by quorum sensing.
Each step in the biolm formation process is
regulated by a different set of genes. For example, genes involved in initial attachment to the
surface are different from genes involved in EPS
production.
The viscoelastic properties of the EPS matrix
play an important role in the mechanical stability
of the biolm, protecting bacteria from antibiotics and other environmental stressors.
Conversely, certain bacterial strains do not
generate EPS and instead disperse directly into
the environment through a process called sloughing. This detachment mechanism can be triggered by various factors, including mechanical
stress induced by uid ow or shear forces.
Additionally, the production of enzymes that
actively degrade the EPS matrix can contribute to
the sloughing phenomenon, enabling these bacteria to efciently release into their surroundings.
For example, Escherichia coli produces
N-acetyl-heparosan lyase; Pseudomonas aerugi-
nosa produces alginate lyase; or Streptococcus
equi produces hyaluronidase.
Even bacteria that do produce EPS can detach
from the biolm and disperse. This process is
known as active dispersal. Active dispersal is
often triggered by environmental cues, such as
nutrient limitation or overcrowding.
During active dispersal, also upregulate the
expression of genes involved in agella and
increase enzymes production to degrade the EPS
matrix. In this way, bacteria break free from the
biolm and are able to move to new locations
[32–36].
42
M. Trevenzoli et al.
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