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crobial properties that can be used on skin,
wound, and mucous membranes [16].
Their mode of action leads to the neutralization of bacterial load activity not necessarily
through a microbicidal activity only: An antiseptic can be effective also by blocking the replication curve of a bacterial agent [17]. Differently
from disinfectants, antiseptics are developed for
application on living tissues, and therefore, these
had to fulll also safety criteria, such as histocompatibility and lack of cytotoxicity [18].
Ideal properties for antiseptics include widespread and rapid bioactivity against bacteria,
fungi, and viruses, no toxicity or damage to the
healthy tissue, and insignicant absorption into
the systemic circulation following external application [19].
Wounds, especially chronic ones, are particularly sensitive to the deleterious effects of infections, and antiseptics are an important component
of the therapeutic strategy in this patient.
5.4 The Bioburden inSkin
andWounds
The presence of bacterial load on healthy skin or
wounds is a physiologic condition not necessarily associated with the development of infection.
Such a condition, also known as contamination,
is characterized by the simple presence of microorganisms on skin or wounds: In this context, the
environment is not helping the replication and the
persistence of those microbes. Therefore, their
detection is at short term, and they are not responsible for a delay in wound healing [20].
When bacteria or germs nd suitable clinical
conditions for their replication, they can overcome host defense mechanisms, achieve a stable
equilibrium on the skin, or better, wound surface,
and begin replicating themselves. The wound
then becomes their host environment: Such process is called colonization. In this case, the presence of bacteria does not elicit an immune
response and therefore does not determine clinical symptoms. The impact of such conditions on
wound healing is still quite controversial but
actually, there is not strong evidence that a simple
colonization could really challenge skin repair
mechanisms [21].
Whenever the balance between the virulence
rate of bacteria and the contrast from immune
host defenses favors the former toward the latter,
an infection can develop. In this context, bacteria
or viruses can spread, progressively invading a
more extensive area causing immune response
and tissue damage. It quickly leads to the development of clinical signs and symptoms, and it
severely affects the wound’s healing pathway
[22].
The factors that inuence host-pathogen interactions and balance are not completely understood [23]. From the host’s side, the most reliable
factor related to the derangement with the predominance of infection is associated with an
impairment in immune system: A typical case is
that of diabetes mellitus, a paradigmatic condition in which patients are more prone to the
developing infections [24].
From a bacterial point of view, many conditions can increase the chances of overcoming
host defenses [25].
The rst factor that must be considered is represented by microorganism species. Not all the
strains have the same ability to determine the
occurrence of an infection: More virulent species
can reduce the immune system’s resistance
threshold. The different potential depends on the
kind of ulcer or clinical status, but a common
condition is represented by the synergistic effect
observable when more bacteria are detectable
contemporarily. The polymicrobial disease is
associated, in any type of condition, with a more
probable development of infection and even
beyond, to a more severe outcome of infection
itself. In diabetic foot infection, for example, the
presence of Gram-positive Cocci, typically
Staphylococcus aureus, and of Gram-negative
Rods, such as Pseudomonas aeruginosa, is more
frequently associated with infection and with a
scarce answer to anti-infective agents [26].
A second important factor, which facilitates
the evolution toward infection, consists of antibiotic resistance mechanisms. These bacterial
weapons can arise from genetic mutations or
gene acquisitions and are related not only to a
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weaker answer to antibiotic treatment once infection has been established, but also to an increased
ability to convert colonization into infection [27].
Eventually, this bacterial property is considered at the same time the strongest obstacle to
infection resolution and the most important sign
of bacterial evolution and overcoming of therapies: the biolm. Biolm is what infectious diseases specialists call “The city of microbes” [28].
Biolm creation is a multistep process that starts
from planktonic cells through the creation of a
micro-colony, up to the nal structure as we
know it. The system is a tridimensional glycoproteic exostructure that bacteria can create when
they x themselves on host cells’ protein scaffolding. It is typically made of many different
bacterial species and congures itself as a multispecies microbial community hosting bacteria
that share their genetic material at high rates. It
should be considered a complex, highly differentiated, and multicultural community, just like our
own city. In this structure, bacteria are protected
from outside and maximize their hurtful effects.
Converting from single planktonic bacterial cells
into a biolm cluster phenotype, microbes’ cells
acquire the ability to easily share genetic elements at accelerated rates [29]. This leads to the
initiation of a tight cell-to-cell signaling, termed
quorum sensing, that is a cell density-dependent
transcriptional regulation system. This system,
comprehensibly enhanced in biolm aggregates,
initiates the protein expression of virulence factors, antimicrobial resistance mechanisms, and
the assault to host defense [30]. All these abilities
lead bacterial population to acquire the resistance
mechanism typical of biolm: tolerance. While
resistance is associated with acquisition of tools
that regulate active mechanisms able to directly
reduce the activity of antimicrobial agents, allowing bacterial replication and growth, tolerance
enables biolm cells to sustain long-term exposure to the antimicrobial agents without loss of
vitality. Biolm can therefore be considered a
defense mechanism. In this context, besides bacterial cells, a pivotal role is attributed to biolm
intercellular matrix [31]. This is not only inert
uid surrounding bacteria, but rather an active
player that chelates or neutralizes many antimi-
crobial agents. If environmental local conditions
become unfavorable, bacteria alone or as little
micro-colony may detach and be carried away
through the bloodstream reaching new targets
with more attractive conditions to colonize. This
possibility is particularly important when antibiotic systemic therapy begins to impact on bacterial survival inside biolm or when the
debridement of the wound is trying to remove it.
Biolm is the most important known mechanism
of wound healing delay. It is a self-maintenance
device for bacterial cells and for mutual protection inside which bacteria can reproduce, grow,
and fortify themselves [32].
Most of our knowledge regarding the wound’s
bacterial burden derives from invitro studies. In
particular, the acquisition of awareness of biolm
characteristics was possible thanks to extensive
laboratory studies where, due to increasing gradient of oxygen and nutrients, the number of bacterial layers detected in biolm is usually increased
when compared to what is detectable in vivo.
This consideration has developed the concept
according to which the border between infection
and colonization in vivo should be set earlier.
Colonization of a wound could be sometimes sufcient to reduce the chance of healing of the
lesion. This condition was rst described in the
nineties and referred to as “critical colonization”
[33]. Critical colonization consists of microbial
populations that actively replicate without being
able to invade tissues or break out an immunological response, however, creating a delay in
wound healing [34]. The term was used to explain
the wide spectrum of conditions ranging from
health status to infection and to modify the scholastic conventional model of relationship between
wound and bioburden [35]. The model of critical
colonization nowadays referred to as “local infection,” or “covert infection” was intermediate to
colonization and infection. In this system,
increasing bioburden was related to clinical predisposing circumstances. This particular status of
critical colonization does not seem to be simply
associated with bacterial load, but mainly with
the ability of immune response [36]. This makes
this status particularly important in diabetic
patients in which immune deciency is one of the
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leading causes of wound infection and in which
the expected signs of local or systemic infection
are often absent or at least late to appear [37].
5.5 Characteristics ofAntiseptics
Antimicrobial agents used in medicine can be
divided into groups: disinfectants, antibiotics,
and antiseptics. Disinfectants are used on inert
surfaces where they are supposed to completely
destroy any kind of microbial population, typically on surgical instruments or elds [38].
Antibiotics are drugs, usually administered
enterally or parenterally, and are carried through
the bloodstream to different parts of the body;
many antibiotic agents have been developed also
for topical application but evidence of their efcacy is still weak [39].
Antiseptics are antimicrobial agents developed to be applied topically on skin, cavities, or
wounds without relevant systemic absorption.
Antibiotics that have been developed to be effective against a specic spectrum of bacteria are
useless against other kinds of microbes such as
viruses or fungi. Antiseptics have instead a wider
range of action, being able to stop or slow down
the growth of many different species of microbes,
including bacteria but also viruses and fungi [40].
The amount of available evidence related to
antiseptics in wound care is substantial but conicting, and reliable data derived from metaanalyses or randomized clinical trials are limited.
High level of evidence regarding effectiveness of
different antiseptics with comparison between
different principles is also scarce [41].
Antiseptic agents can be delivered through
different formulations, in particular, in case of
wound treatment. These can come in the form of
liquids applied directly on skin or wounds or can
impregnate a topical dressing, in combination
with other wound-treating effects like protection
or absorption of exudate [42].
The bioburden control mediated by antiseptics
can be divided into active or passive. Antiseptics
that exert an active control are those which inhibit
growth and proliferation of microbe population
on the wound bed, whereas if the agent simply
helps remove microbes and related material without any impact on microbial ora, it is characterized by a passive control process. Both active and
passive modalities are available for all kinds of
antiseptics [43]. If we consider advanced dressings, for example, despite the vast majority of
them determine a release of antiseptic components onto the wound bed, some recently developed dressings exploit a hydrophobic mechanism
consisting of creating a bond between dressing
and bacterial cells, taking advantage of the negative charge present on the surface of microbial
cells. The nal result is that bacteria and their
compounds are absorbed by the dressing through
a purely physical mechanism without release of
any substance on wound bed or treated tissues
[44].
This characteristic is particularly important
considering that one of the most important limitations in using antiseptics consists in the cytotoxicity of its chemical components. The
concerns about this possibility were raised in
1915 and are not yet completely solved: The
achievement of a wide-range activity is unfortunately associated with some extent of tissue damage [45]. Therefore, a punctual analysis of
cytotoxicity level in animal models or invitro in
keratinocytes, broblasts, lymphocytes, and neutrophils is necessary and mandatory before allowing the clinical use of the active principle [46].
Besides the absence of cytotoxicity, the ideal
antiseptic should be associated with very low levels of sensitization. Hypersensitivity or allergic
reactions are very rare when using antiseptic
solution but represent one of the most important
parameters to be monitored because of the risk of
anaphylactic shock in extreme cases [47].
From a functional point of view, the “ideal
antiseptic” should be characterized by biocidal
activity against a wide range of microbial agents.
The biocidal activity can be obtained through
oxidation of bacterial protoplasm, coagulating
microbes’ proteins, thus denaturizing it or eventually increasing the permeability of microorganism wall to external toxins. This kind of action
should be preferred to inhibition of microbes’
replication or growth, for its permanent longterm effect. The main limitation to this biocidal
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power is represented, unlike what happens for
disinfectants, by the pursuit of an equilibrium
between activity on microbes and damage of
healthy tissues. The level of biocidal activity is in
part an intrinsic characteristic of the antiseptic
principle but is strongly inuenced by many different conditions. Part of these conditions are
related to the microorganisms involved: Beyond
the different susceptibility of the various species,
the biocidal activity level is inuenced also by
microbial load and by the resistance to the antiseptic itself [48]. Many microbes have indeed
developed the ability to inactivate or degrade the
antiseptic principle thus overcoming its action.
This event is rare if compared to the same phenomenon in antibiotic treatment, but is responsible for the reduced effectiveness of many
antiseptics in specic clinical settings. Among
microbial factors, also the presence of biolm
strongly decreases the biocidal power of the
already described mechanisms of acquisition and
transmission of bacterial resistance. Other factors
inuencing the level of biocidal power are associated with the application modalities of the antiseptic: Proper concentrations of active principle,
for example, if not respected, can reduce its
effectiveness while increasing the onset of resistance phenomenon [49]. Changes in pH, temperature, or length of application can also modify
the level of biocidal action. The last one, in particular, can be prolonged obtaining an increase in
biocidal activity until the achievement of optimal
application time. Beyond this time, the evaporation of active principle or of its solvent could
inactivate the antiseptic [50]. The limit of this
consideration is that the optimal application time
cannot be uniquely dened, for it varies on different tissues and secondarily because, before this
golden time, some side effects can appear, such
as risk of maceration on wound bed or perilesional tissues. Eventually, the presence on the
wound bed of different biological materials, such
as blood or purulent material, can severely modify the ability of the antiseptic to exert its biocidal
activity [51].
Particularly relevant is the spectrum of antiseptic action: The effectiveness of the agent is
closely related to the range of microbes strug-
gled. While this is easily applicable in disinfectant for inert surfaces, in which we can increase
the strength of antimicrobial action with the only
limit of chemical properties and technologies,
more cautions must be used in antiseptics [52].
These principles can indeed increase their effectiveness only until the threshold of risk for tissue
damage. For these reasons, antiseptics are distinguished in low and intermediate power level,
while high level is reserved for disinfectants.
Low-level antiseptics act against most bacteria
but only some viruses and fungi are generally
ineffective in destroying spores or alcohol-acidresistant bacilli. Antiseptics are instead considered intermediate level if able to ght all bacteria,
most viruses and fungi, and more resistant bacilli;
also, this class of agents is usually ineffective
toward spores or vegetative status bacteria [53].
From a practical point of view, the development
process of antiseptics should aim for active principles with a short latency of action and a long
duration, better if easy to apply. In recent years, a
great attention has been driven on resource consumption, especially in areas where demonstration
of efcacy still lacks evidence. In such a context,
the achievement of comparative data on costs/
effectiveness of antiseptics would be welcomed,
but it is anyhow needed common practice to allow
the extensive use of these products inside healthcare system and in daily clinical practice [54].
Antiseptics have been developed and validated for topical use, on skin, wounds, or inside
cavities. The action must be exerted topically on
application surfaces. For this reason, the systemic
reactions to this product are not extensively
known but we are aware that an excessive absorption of the product may lead to development of
resistance, thus severely reducing the efcacy of
antiseptic. Eventually, the achievement of high
concentrations inside bloodstream can easily
increase the risk of patients’ sensitization and the
occurrence of an allergic reaction also characterized by systemic signs. It is therefore necessary
for antiseptic compounds to have low or absent
penetration through the deeper tissue layers [55].
There are also some ancillary characteristics,
however, very important, that should be required
for antiseptic effective agents. First of all, pro-
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longed chemical stability is necessary. The solution should be stable in clinical environment for a
long period before the opening of the packaging.
Cost- effectiveness ratio is also important from a
resource-saving point of view (Table5.1).
The solution should not contain factors able to
inhibit healing process. The use of antiseptics in
wounds is particularly important, and their action
should consist rstly in bioburden control.
However, it is important to focalize that, as for
any other local advanced therapy, the role of antiseptics should be perceived as a corollary to be
applied when systemic conditions challenging
wound healing are completely addressed and
solved. In this setting, antiseptics should not hinder but rather encourage wound healing [56].
Eventually, antiseptics should not induce resistance to their chemical components. The occurrence of resistance phenomena in antiseptics, more
than in antibiotics, is commonly associated with a
reduction of cellular input related to hyperexpression and hyperactivity of efux pumps that block
entrance and increase excretion of the antiseptic
[57]. This possibility is particularly frequent in
multi-bacterial conditions and, in particular, in
case of the presence of biolm [58]. In such conditions, many bacteria have the spontaneous ability
to up-regulate multidrug efux pumps: typically,
qacA in Staphylococcus aureus or mexAB-oprM in
Pseudomonas aeruginosa [59]. It is therefore
important not only to restrict antibiotic use, but
also to monitor and eventually reduce the use of
antiseptics in health care [60].
Table 5.1 Characteristics requested for antiseptic agents
[51–56]
The characteristics of the “ideal antiseptic”
Biocidal activity
No cytotoxicity effect
No patients’ sensitization or allergy reactions
Broad spectrum of action
Rapid-acting and long effect
Low absorption level
Easy application
Good cost-effectiveness ratio
Chemical prolonged stability
No hindering effects for healing
No or low resistance induction
5.6 Indication ofAntiseptic
Treatment
5.6.1 Antiseptics inSurgery
As already discussed above, the main goal of antiseptics is to obtain a reduction of bacterial load on
application site. In the medical eld, this is particularly important on surgical sites. The use of antiseptic agents in operatory eld, to prepare the skin
before the incision, is with no doubt the rst application of this kind of product. Patients’ skin at the
operation site is routinely cleansed with antiseptic
solutions in the operating theater before surgical
incisions are made [61].
As expected, this is most important in clean
or scarcely contaminated surgery where the risk
of infection is lower, but the consequences of a
surgical site infection can be dramatic or even
lethal [62].
Surgical site infection rates in the month following clean surgery range from 0.6% to 5%.
This complication represents one of the most
challenging issues in surgical techniques and a
main source of healthcare costs. Surgical infection can often lead to patients’ death or, in case of
resolution, the long journey toward it carries a
huge impact in terms of quality of life. This social
cost is even wider than the economic burden for
the public health system [63].
To optimize the effectiveness of antiseptic
measures, the Centre for Disease Control of the
health administration of the US has drawn up a
specic procedure composed of different steps.
First of all, the size of the prompted area should
be sufciently wide to include any potential site,
even when far from the main expected incision
[64]. The solution should then be applied in concentric circles starting from the center of the
lesion then moving with a centrifugal direction
toward the peripheral area. After application, the
solution should be left to dry, especially in case
of use of an alcoholic solution [65].
The effectiveness of preoperative skin preparation is thought to be dependent on all the criteria mentioned above and related to the antiseptic’s
intrinsic properties (chemical composition, its
concentration, and application method [66]).
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Despite all these considerations, the actual
efcacy of skin antisepsis in reducing surgical
site infection is still unclear and the relative
effectiveness of different agents is still debated.
The scientic evidence concerning this issue is
not unambiguous; therefore, often clear indications cannot be given [67].
Future trials are strictly needed to provide
more reliable information to further decrease the
prevalence of such a dramatic complication of
surgery. Denitive and hopefully conclusive data
on this issue could be achieved through large randomized controlled trials that compare different
antiseptics [68].
5.6.2 Antiseptics inWound Healing
The amount of published evidence on wound
care is huge but conicting and high-quality evidence, derived from meta-analysis or randomized
trials, is scarce. Few interventions have produced
solid conclusion regarding the effectiveness of
antisepsis. A product’s real effectiveness should
be rst proven by invitro activity, then exceed
the clinical challenge in wound healing. Only
after following these steps can the evidence
achieved be considered of impact on decisionmaking actors [69].
A major issue regarding clinical evaluation
of the use of antimicrobials in wound healing
is the lack of strict consensus concerning
infection classification, precisely in the definition of “infected wound,” and the criteria to
define the resolution of this infection. While it
is clear how the presence of microbes is not a
sufficient criterion for the wound to be considered infected, the parameters to define this
condition are still not well established [70].
Most patients suffering from chronic wounds,
especially diabetic patients, rarely display any
early signs of local infection, often detectable
only in advanced disease stages because of
their impaired immune system [71]. In those
cases, secondary or suggestive signs such as
smell, undermined edges, ineffective granulation tissue, or prolonged pain can aid in infection diagnosis [72].
The challenge in diagnosing local infection
explains the problems in evaluating the actions of
antiseptics on the outcomes. Given that further
and more conclusive studies should be carried
out to better understand the effect of this class of
products, dening the golden endpoints for these
studies might be particularly hard [73].
To this day, the majority of the studies have
focused on management of local infection. The
prevention of infection is probably the most frequently evaluated parameter. Many studies have
been suggested, and many reviews have tried to
collect conclusive information. For example, the
overall analysis demonstrated weak evidence that
silver-releasing dressings can reduce the risk of
infection in chronic pressure ulcers, for the sample sizes that were too small to claim conclusive
statistical evidence [74]. Actually, there is little
evidence to support the use of antiseptic topical
treatments to prevent wound infection, particularly in diabetic patients. There is also little evidence to support the choice of one antiseptic
instead of another, in attempts to prevent wound
infection [75].
Regarding the impact of antiseptic use on resolution as well as recurrence of infection, the few
available data are not conclusive because of the
problems related to the denition or the criteria
that should be used to investigate the ending of an
infectious episode [76].
To be able to properly assess the impact of
antimicrobials in wounds, we need a more adequate selection of endpoints and a new set of
tools to evaluate those endpoints. As indicated
in every study investigating wound treatment,
the gold standard in terms of outcome is represented by wound closure: Parameters such as
healing rate and healing time can be considered
the hardest outcomes to achieve [77]. These
endpoints clearly represent the main outcome
but must be investigated through sufciently
well-designed studies that can validate the correlation between antimicrobial intervention and
clinical outcome. The weakness of this endpoint
has been conrmed also in Guidelines produced
by the International Working Group on Diabetic
Foot that stated how dressings containing surface antimicrobial agents should not be used
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with the sole aim of accelerating healing of an
ulcer. In fact, if we were to consider this kind of
outcomes alone, no therapy could ever be considered effective [78].
The only available alternative is to consider
evolution of infection as the best outcome.
Clinical infection of wounds is caused by nonhealing wounds, increased treatment times,
higher expenses, increased suffering, and risk
of severe complications. For this reason, infection is a clinically important factor for healing.
In diabetic foot patients, it represents the most
frequent criteria for amputation. The critical
point is the identification of the best modalities to define the presence of infection: It
should be established relying on objective
clinical parameters [79]. The development of
tests and techniques that can improve tissue
sampling of analysis and imaging technology
and the progress in cellular and molecular
biology have enabled, in a search field which
is developing in these years, the development
of more “objective” wound infection outcome
parameters that relate to both the wound condition and the treatment intervention performed. One of the most important goals of
this technical implementation should be represented by our ability to test microbial susceptibility inside biofilm. The new possibilities,
such as continuous flow cell systems, analysis
of colony biofilms, and drip flow or rotating
disk reactors, have demonstrated a real reliability but unfortunately are not yet available
outside experimental settings [80].
5.7 Characteristics ofCommonly
Used Antiseptics
5.7.1 Chlorhexidine
Chlorhexidine was rst synthesized in 1950. It is
an organic cationic biguanide whose structure
consists of a linear-chain hexane. It is composed
of two biguanide parts, which act as cations and
are stabilized associating them to two anions that
can be chloride, acetate, or gluconate ions and are
positioned at the end of hexane chain. This asso-
ciation allows to stabilize chlorhexidine and render it partially soluble in liquids [81].
A considerable amount of research has been
undertaken on the mechanism of the antimicrobial action of this important bis-biguanide
despite as often happens in antiseptics and local
therapies; overall, the conclusiveness of data is
scarce [82].
Molecular structure and positive charge confer chlorhexidine a great afnity for skin and
determine its prompt effect [83].
Chlorhexidine binds to cell wall and membrane and inhibits both membrane-bound and
soluble ATPase as well as of pumps for potassium uptake. ATPase inhibition is realized only at
high chlorhexidine concentration, and this suggests that the enzyme is not the primary target of
the antiseptic solution. It seems indeed that primary and more important effects are associated
with collapses of membrane potential, more
focalized on sodium and potassium cotransporter
[84]. The result is that chlorhexidine crosses the
wall and the membrane of microbes, presumably
by passive diffusion, and subsequently attacks
the bacterial cytoplasmic membrane. This is followed by leakage of intracellular constituents
and, as the concentration grows, to the coagulation of intracellular organelles and eventual cellular lysis and death [85].
Its action is strongly inuenced by concentration: At low concentrations, it is bacteriostatic,
becoming bactericidal at higher concentrations.
Even higher concentrations of chlorhexidine
cause coagulation of intracellular constituents
with a consequent reduction in leakage and in
cellular death. There is therefore a biphasic trend
on cellular action and therefore on antiseptic
effectiveness [86]. Chlorhexidine is limited also
by pH changes: Its optimal range of action is
realized from 5 to 7, and the effectiveness is
greatly reduced above 8 [87].
Chlorhexidine displays a wide range of coverage being particularly effective on both Grampositive and Gram-negative bacteria. For the
cellular mechanisms reported above, it showed a
biphasic trend while a progressive increase of
concentration determines before an increased
effect on microbes’ cells and then, when concen-
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tration continues to increase, a reduction on the
biocide action [88]. It is usually not sporicidal
even at high concentrations, although a clear sporicidal effect is achieved at elevated temperatures
probably for changes that occur in the spore
structure and allow an increased uptake of the
biguanide. Mycobacteria are generally highly
resistant to chlorhexidine. The effects of
chlorhexidine on yeast and fungi present the
same double-phase trend reported for bacteria.
The antiviral activity of chlorhexidine is variable
and still not well-dened, probably because it
presents a high variability among bacterial species [89].
Toxicity episodes as well as sensitivity reactions are very rare. The absorption through skin,
wound, or mucous membranes is irrelevant. The
prolonged use of the antiseptic can provoke
reversible dark coloring of the teeth, which disappears on suspension and in atopic subject have
been reported cases of eczematous contact dermatitis [90].
5.7.2 Povidone-Iodine
Povidone-iodine is a complex of polyvinylpyrrolidone, hydrogen iodine, and elemental iodine. Its
solution of iodophors or iodine-releasing agents
had overcome the main limits of iodine [91]. For
about two centuries, this component has been
used in antisepsis pure with severe damage to
vital tissues; when tried in solution, it presented a
dramatic reduction of its power until the complete loss of its antimicrobial efcacy. The introduction of iodophors resolved these difculties
[92].
Different solutions present different compositions, both in terms of concentration and in terms
of different percentages of the various active
principles. In most used solutions, the carriers are
neutral polymers of polyvinyl pyrrolidone [93].
The antimicrobial action is rapid; it penetrates
microorganisms attacking key groups of proteins,
in particular, the amino acids cysteine and methionine, nucleotides, and fatty acids. It acts via
iodination (a form of halogenation) to oxidize
lipids of the cell membrane and to form salts with
microbial proteins. From a cellular point of view,
it promotes wound healing through increased
expression of TGF-β, neovascularization, and reepithelialization [94].
Povidone-iodine can claim a broad spectrum
of activity against Gram-positive and Gramnegative bacteria, including bacterial spores and
Mycobacteria, fungi, and viruses. It is particularly active against all forms of nosocomial infection, the group of the microbes known as “Eskape
pathogens” meaning Enterococcus faecium,
Staphylococcus aureus, Klebsiella pneumoniae,
Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species [95]. It has been
demonstrated to be highly effective also in eradicating biolms, including MRSA, Klebsiella
pneumoniae, Pseudomonas aeruginosa, and
Candida albicans forms [96].
No important antimicrobial or cross-resistance
has been reported. It presents reduced activity at
basic pH or in the presence of alkalis and incompatibility with acetone, hydrogen peroxide, and
mercury compounds, and all these conditions can
mimic an apparent tolerance [97].
Allergic reactions are very rare but its usage
should be particularly carefully, until avoiding if
possible, in patients with diagnosed thyroid
hyperfunction or who will undergo diagnostic
procedures involving the use of iodinated contrast media [98].
5.7.3 Polyhexamethylene
Biguanide
Polyhexamethylene biguanide (PHMB) is one of
the most promising antiseptic substances available today. It is a cationic biguanide polymer rst
synthesized in the 1950s, whose chief monomer
is closely related in structure to the bisbiguanide
chlorhexidine gluconate. It is colorless, odorless,
and non-corrosive, and is soluble in water and
alcohol [99]. From a chemical point of view, it is
a strong base and therefore interacts with acidic,
negatively charged phospholipids in the bacterial
membrane, leading to increased uidity: It
increases the distance between the lipid molecules
of the membrane and affects the proper function-
5 Principles ofAntiseptic Treatments
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ing of ion pumps, various enzymes, and bacterial
cell receptors [100]. Furthermore, it stiffens the
liquid bilayer membrane, leading to an increase
in its permeability and the subsequent loss of
integrity, quickly leading to microbes’ death. It
can also block microbial attachment to cell surface and transfer itself inside the cytoplasm interfering with bacterial metabolism. Neutral
phospholipids on the other hand are little or not
affected by PHMB, its maximum activity occurs
at a pH value between 5 and 6, and these characteristics explain its high therapeutic range and the
low toxicity against human cells [101].
Due to its nonspecic, strong interaction,
PHMB has a broad antimicrobial spectrum,
including Gram-positive and Gram-negative bacteria, plaque-forming and biolm-building bacteria, spore-forming bacteria (but not bacterial
spores), intracellular bacteria, and fungi. PHMB
has been demonstrated to be able to inactivate
invitro HIV-1 [102] and HSV [103]. In vitro, it is
able also to dissolve brin plaques [104].
It is well-tolerated and used topically on
wounds, skin or eyes, and mucous membranes or
ciliated epithelium. It seems completely nonabsorbable through skin or wounds but due to its
binding to cellular surface, its action is sustained
over hours. PHMB is compatible with acids, quaternary ammonium compounds, and neutral
detergents but incompatible with anionic detergents, soaps, and alkyl sulfates. Strong inorganic
bases and complex phosphates lead to its precipitation [105].
To this day, no cases of resistance have been
reported, nor have sensitizing episodes. PHMB
seems to carry only a slight allergic risk also in
two not conrmed cases of possible anaphylactic
reaction that has been reported some years ago in
intraoperative usage. No reaction or sensitizations have been reported in patients with chronic
wounds [106, 107].
5.7.4 Silver
Silver compounds have been perhaps the rst
modern idea of antiseptic product. In the large
family of “Silver compounds,” we can allocate
three different elements: silver ion, silver nitrate,
and silver sulfadiazine. Less frequent are silver
oxide and silver collagen. Silver-containing
products require the release of positively charged
silver ions in order to exhibit antimicrobial activity, and this conversion process is thought to be
facilitated by interaction of the silver contained
in wound dressings with aqueous media on
wounds [108].
Probably, due to its long usage as antimicrobials, since the seventeenth century, silver and its
compounds can claim a large amount of studies
investigating its effectiveness in many different
elds of application [109]. Wound healing, burns,
dental surgery, vascular catheter access point,
and eye infective disease are only the most important settings in which silver dressings have been
tested with variable success and different reliability. This large amount of papers is rendered less
effective by the heterogeneous nature of the evidence, and also a Cochrane meta-analysis concluded that there is insufcient evidence to
conrm whether silver-containing products can
promote wound healing [110].
The mechanism of the antimicrobial action of
silver compounds is closely related to their interaction with thiol groups: The silver ions, in particular, bind to the sulfhydryl group of amino and
carboxyl groups of amino acids on microorganism surfaces, also if other target sites remain a
possibility. This linking determines the denaturation of proteins and destruction of the cell wall
with complete loss of membrane functions. Silver
is also specically able to inhibit cell wall metabolism and electron transport as well as the respiration chain [111]. The physical result is that
bacterial cells increase in size, and the external
and cytoplasmic membranes exhibit structural
abnormalities, although without any blebs. It
helps penetration of silver ions into the nucleus,
where they interact with nucleic acids: preferentially with the bases in DNA rather than with the
phosphate groups, although the signicance of
this in terms of its lethal action is unclear [112].
At lower concentration, silver exhibits bacteriostatic action, while when increasing concentration, the action becomes bactericidal. In
particular, silver has demonstrated bactericidal
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activity against Gram-negative and Grampositive bacteria and may also target fungi and
viruses. Bacterial resistance to silver has been
documented and is supposed to be encoded by a
plasmid [113]. This can be particularly impacting
on silver effectiveness cause in polymicrobial
infection determining biolm creation; the transmission of plasmid among bacteria can be common and easy thus conferring to wide population
of microbe’s silver resistance despite this silver
seems to be effective against biolm-producing
bacteria [114].
Studies have showed a cytotoxic effect by
causing a severe delay in re-epithelialization. In
vivo, this effect seems predominant against granulation tissue and its prevalence increases when
silver compound concentrations rise to reach
more effective bactericidal ones [115].
Moreover, silver has a good tolerability prole. When increasing concentration, it has been
shown to be absorbed, mostly in conjugation
with protein and then deposited in human tissues,
with higher levels in skin, kidneys, eyes, brain,
liver, and bone marrow. In extreme cases can
occur a rare cutaneous condition resulted by
excessive or chronic use of preparations containing silver, called Argyria. The most characteristic
symptom is the discoloration of the skin into blue
or blue-gray, especially in sunlight-exposed areas
with any evidence or pathological tissue damage
or danger to life [116].
5.7.5 Hydrogen Peroxide
Hydrogen peroxide is a highly active peroxide
that forms highly reactive free hydroxyl radicals.
These radicals attack and oxidize essential cell
components, including lipids, proteins, and
nucleic acids, which results irreversibly altered.
Its activity level is traditionally expressed as the
total volume of oxygen release, and solution
commonly used for antisepsis has a 3% weight/
volume concentration [117]. Pure solutions are
generally stable but easily degraded by metal
ions, alkaline, or oxidizable substances, as well
as from light, heat, and agitation. For this reason,
it is not suggested to mix it with other antiseptics
and most solution contains stabilizers to prevent
decomposition [118].
Hydrogen peroxide exerts a greater activity
against Gram-positive than Gram-negative bacteria despite that the presence of catalase or other
peroxidases in these organisms can determine
occurrence of tolerance at lower concentrations.
For these reasons, when used against fungi,
viruses, or bacterial spores, higher concentration
and longer contact times are needed [119].
In addition to being a broad-spectrum agent, it
has a rapid onset of action and low cost, which
made it an attractive option in the past. In recent
times, its use has been limited to skin, and wound
tissue toxicity is particularly dangerous in case of
highly concentrated solutions [120].
5.7.6 Superoxidized Solutions
Superoxidized solutions are made from sterile
water at neutral pH through an electrochemical
procedure consisting in electrolysis of water and
other chemical compounds such as sodium chloride, sodium hypochlorite, hypochlorous acid,
hydrogen peroxide, ozone, chlorine dioxide, and
sodium carbonate. The process produces reactive species of chlorine and oxygen [121]. The
result is a sodium chloride solution at neutral
pH, rich in free oxidized radical. Many superoxidized solutions have been introduced in recent
years, each of which characterized by a peculiar
composition, modality of usage, and spectrum of
action [122].
Considering the general low reliability level of
studies evaluating the effect of a single-specic
antiseptic on infection outcomes, superoxidized
solutions had been studied in two different singlecenter randomized controlled trials [123]. These
papers, which compared these solutions with
other topical antiseptics in the management of
post-surgical diabetic foot, demonstrated a signicant improvement in terms of infection control and wound evolution [124].
Superoxidized solutions elicit cooperation
from neutrophils to easily penetrate the bacterial
wall and thus exert their biocidal activity, which
is about 80 times stronger than a single nega-
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