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5 Principles ofAntiseptic Treatments
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45
tively charged ion, typically hypochlorite. These
physiochemical mechanisms act in two ways: on
one side physically damaging the cellular membrane of microorganisms inactivating their
defense mechanisms and on the other side modifying the biolm microenvironment [125]. The
use of these antiseptics also determines morphological changes to the extracellular polymeric
substance matrix, promoting the exposure of
planktonic bacteria and making them more accessible to solutions’ action [126].
These solutions exert a multi-factorial modulation of the wound microenvironment that create
a stimulus to granulation tissue deposition
improving, eventually, wound healing [127].
Their actions, in parallel with natural host
defenses, make superoxidized solutions able to
ght microbes while preserving eukaryotic cells.
For its mechanical properties, these solutions act
rstly as cleaners of skin and wounds removing
cellular debris. Furthermore, present a bactericidal activity against Gram-positive and Gramnegative bacteria also multi-resistant and
especially inside biolm environment. Sparing
host cells, these solutions have negligible levels
of cytotoxicity [128].
Considering that post-surgical wounds represent one of the main targets of superoxidized
solutions, recent trials have explored association
with negative pressure wound therapy. These two
therapies present a synergistic action in controlling exudate, reduce bacterial load, and promote
granulation tissue, thus increasing healing chance
[129].
5.7.7 Honey
Honey was used in traditional medicine to treat
wounds until the advent of modern medicine
when it was neglected. The rising of global antibiotic resistance has forced the development of
new therapies as alternatives to ght infections.
Consequently, honey is experiencing a comeback for antimicrobial and wound healing applications [130].
Natural honey is composed of around 82% of
water, carbohydrates, proteins, phytochemicals,
antioxidants, and minerals. It contains furthermore a wide range of active compounds, including avonoids, organic acids, phenolic acid,
vitamins, and enzymes [131].
The predominant antimicrobial activity of the
majority of types of honey can be attributed to the
generation of hydrogen peroxide. This is produced by the enzyme glucose oxidase for oxidation of glucose into gluconic acid and secreted
into nectar by bees [132]. Other important antimicrobial features are associated with nonperoxide activities of honey. First of all, low
water content prevents and controls the growth of
bacteria on the wound surface and, for osmotic
effect, helps transport oxygen and nutrients from
the deep tissue into the wound area and causes
uid ow that ushes slough, debris, and necrotic
tissue as well as microorganisms out of the
wound [133]. Furthermore, honey presents a low
pH that creates an acidic environment able to
increase tissue oxygenation [134]. Other functions helping wound healing are associated with
the presence of phenolic compounds and avonoids, in particular, glyoxal, 3-deoxyglucosulose,
and methylglyoxal, that remove free radicals and
bee defensin-1 [135], eventually, also a mechanic
action: Honey is a viscous uid and its jelly consistency creates a surface layer over the wound
that inhibits the entrance of bacteria and protects
the wound from dehydration [136].
The large number of amino acids helps wound
healing also independently from antiseptic action
through a power stimulus to broblasts and collagen formation. It also seems to promote angiogenesis [137].
Two principal types of honey are commercially approved: The medical-grade honey exerts
its action mainly through a non-peroxidase activity, and Manuka honey, holding a strong peroxidase action [138]. This specic kind of honey is a
monooral type derived predominately from the
nectar of the Leptospermum scoparium plant, a
New Zealand tree, that demonstrated to hold
superior antimicrobial efcacy over other honey
sources [139].
Honey can boast about an antimicrobial activity
against Gram-positive and Gram-negative bacteria,
including multi-resistant species. There is also evi-
46
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E. Iacopi et al.
dence regarding antifungal activity and also against
many viruses: In particular, some of the avonoids
present in honey, in particular, chrysin, should be
able to prevent HIV-1 activation [140].
5.8 Conclusions
A long journey has taken us from ancient superstitions to modern technological evolutions, starting from wine and herbs we have reached
increasingly effective synthetic compounds. The
science of antisepsis and local infection control
reproduces the evolution of scientic knowledge
better than many other medical branches. And
more than other elds of medicine, it still feels
the need for standardization in clinical practice
and even before in research.
The management of local infection can today
rely on a wide and varied range of highly technological tools that are safe and effective and are
applicable in a large variety of clinical settings.
In the last decades, we observed a huge expansion of our possibility of choice. New active principles have been synthetized and other,
already-known ones, have been adapted to implement their performances.
This becomes even more important when, like
nowadays, it is necessary to tailor these treatments to the patient in order to maximize results
while controlling costs. This will allow not only
to better manage healthcare costs but also to
guarantee patients’ better chances of healing in
the shortest possible time, thus reducing their
expenditure in terms of quality of life.
To obtain these results, pharmaceutical chemistry has provided us with compounds that are
increasingly tolerated and with safety proles in
terms of side effects close to perfection.
The baton now passes to clinicians. If it is true
that clinical and medical researches provided us
with a series of particularly effective weapons, it
is equally true that we are responsible for the correct use of such instruments.
An accurate, effective, and prudent selection
represents a fundamental choice for our patients
as well as inserting these tools in the optimal
therapeutic path. The effectiveness of a correct
antisepsis covers its function only inside a welldened multidisciplinary integrated approach.
This pathway should be applied quickly and
effectively for an optimal local and systemic
control of the patient’s clinical condition
(Table5.2).
Table 5.2 Summary of characteristics of principal antiseptic solution (refs in the text)
Cellular
Antiseptic Introduction Mode of action Target bacteria
Chlorhexidine 1954 Penetrating by wall
Povidone-iodine 1956 Iodination of amino
Polyhexamethylene
biguanide
Silver Seventeenth
1994 Stiffening of bilayer
century
pumps, it coagulates
cytoplasmic
organelles
acids, lipids of cell
wall, and
nucleotides
membrane
increasing
permeability and
loss of integrity
Interaction with
thiol group:
Denaturation of
protein and cell wall
S. aureus
Ps. aeruginosa
E. coli
S. aureus
Ps. aeruginosa
S. epidermidis
S. aureus
Ps. aeruginosa
E. coli
(++biolm)
In vitro
inactivation of
HIV and HSV
S. aureus
Ps. aeruginosa
MDR bacteria
Fungi, viruses
toxicity
Fibroblasts Risk of
Fibroblasts Renal and
Fibroblasts – Very rare
Fibroblasts
and
keratinocytes
Systemic
toxicity Allergenicity
Rare
anaphylactic
reactions
Common
thyroid
dysfunction
Argyria Rare
5 Principles ofAntiseptic Treatments
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Table 5.2 (continued)
Antiseptic Introduction Mode of action Target bacteria
Hydrogen peroxide 1887 Free hydroxyl
Superoxidized
solutions
Honey Ancient eve Production of
1827 Reactive species of
radicals bind thiol
groups in protein,
lipids, and nucleic
acids denaturing
them
chlorine and oxygen
penetrate and
irreversibly damage
bacterial wall
hydrogen peroxide
that damages
cellular components
and through a low
pH increases tissue
oxygenation
S. aureus
Ps. aeruginosa
S. epidermidis
Fungi and viruses
S. aureus
Ps. aeruginosa
MRSA
E. coli
(++biolm)
S. aureus
Ps. aeruginosa
MRSA
Cellular
toxicity
Fibroblasts
(++ at high
concentration)
–
(eukaryotic
cells saving)
– – Very rare
Systemic
toxicity Allergenicity
Embolism Rare
– Rare
47
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The TIMEH Protocol
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ClaudioLigresti
6
The best way to shorten the healing time is an
accurate staging of the lesion [therefore a proper
understanding of the gravity of the wound] and
then the decision on the most appropriate therapy. In the last 20 years, there have been great
strides in the understanding of the biological
mechanisms involved in repairing wounds, so
now more than ever we have the means necessary
to assume a time of complete healing as accurately as possible [1].
Our paperwork tends to make available to the
medical staff a valid model showing the most
correct treatment for a certain type of injury that
can allow us to predict the healing time.
All patients were treated with one of the principals randomly choosing among those listed
with intervals recommended by the type of
wound. The study duration was 6months. In our
proposal, we considered a whole TIME, pain
conditions, environmental conditions, and lifestyle to get a severity index [IG], which allows us
to have a prediction of healing time.
As shown by Kramer etal. [2], the size and
depth of pressure ulcers are good predictors of
healing: As lower the ulcer grade, the greater will
be the chance of recovery. We then moved on to
the study of pain considering parameter with
score 1 as no pain and mild pain score with value
C. Ligresti (*)
Maria Pia Hospital, Torino, Italy
2 [stimulated during the dressing value and 3 to
intense pain [without stimulation] [3].
Finally, we look at general conditions and
environmental factors [4–19]. At this point, in
our algorithm we add the time and the EBF [factors, anamnestic, social, and clinical] and multiply them for pain and volume: The value obtained
is our gravity index [GI].
TIME 116EBF 118PAIN1 3
×
The healing time [TH], as already stated, also
depends on the therapeutic strategy undertaken:
The numerical value is in direct relation to the
therapy. The TH is equal to IG and will not
change if the therapeutic choice [soft] resides on
the left side of the table, which is 60 days]
(Table6.1).
We can change the situation by customizing
the type of therapy on the individual case. In this
way, we can modify the healing time [20]. Take,
for example, a lesion volume between 50 and
100cm3.
We can have lesions T0, I0, M0, E0, thus
devoid of necrotic tissue, bacterial contamination, exudate, and with re-epithelialization
rate>75%, or lesions T4, I4, M4, and E4 with
100% of necrotic tissue infections, exudate, and
the absence of spontaneous new epithelialization:
With the same situation, in any case, the choice
of therapy will change the history of the lesion
and the timing of healing.
−− −
VOLUME2 32 IG
[]
=
−
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023
M. Maruccia et al. (eds.), Pearls and Pitfalls in Skin Ulcer Management,
https://doi.org/10.1007/978-3-031-45453-0_6
53
54
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Table 6.1 Soft: not aggressive treatment
T
Non-viable tissue
I
Infection or inammation
M
Exudate
And maceration
E
Delay of
Epidermization
Absent0Present
Absent0Present
Absent0Present
Absent0Present
1
25%
1
Contamination
1
Low
1
25%
Present
2
50%
Present
Critical
2
Colonization
Present
2
Abundant
Present
2
50%
Present
3
75%
Present
3
Critical
Colonization
Present
3
Abundant and
Color
Present
3
75%
C. Ligresti
Present
4
100%
Present
4
Infection
Present
4
Abundant, color
and smell
Present
4
100%
For exemple, choising a soft treatment [such
as autolysis, we have a signicant improvement
of the lesion as low as 25 days [21–23]. This
time can decrease, even drastically, by level up
in the type of strategy used: The time passes to
20days with osmosis, 15 days with the larvae,
until a day using hydrotherapy, ultrasound, or
surgery.
Regarding the I: We passed from an improvement of 55days with saline [strategy blander], to
21 days of antiseptics/dressings with silver/
NPWT [negative pressure wound therapy] up to
7 days after the surgery/ antiseptics/antibiotics/
NPWT.
The M represents an increase in 55days with
hydrogel/hydrocolloid and hydrober 28 days
with up to 10days of the surgery.
Finally, the E: new epithelialization from 100
days with advanced medications, 45 days with
VAC and only 10 days with autologous graft
[24]. Time of Healing: The numerical value is in
direct relation to the selected therapy. It is equal
to that of IG patient, and its value will not change
if the therapy choice [soft] is on the left side of
the table therapeutic.
MA: medium-aggressive treatment; A: aggressive treatment report of the results obtained with
the averages of the healing times on a number of
22 patients, obtaining a slightly higher percentage of error of 10% in the prediction of healing
time.
Our protocol GI is 50 and ASA 50, and ASA
is 4–5 with infection between 1 and 2 as soft
therapy. GI is >50 and ASA is 4–5 with infection between 3 and 4 as medium aggressive
therapy.
Nowadays, various systems try to give a prediction of healing time, taking into account various parameters. Troxler et al. [20] studied the
importance of periodic evaluations of the wound,
accompanied by measurements of its surface, for
the identication of potentially hard-to-heal
wounds.
The early detection of a reduction in the size
of the wound is set by measuring the progress of
the margin [epithelial advancement]. Phillips
et al. considering the percentage reduction in
venous ulcer area found that in about 77% of
cases, healing outcomes could be predicted based
on a wound size reduction of more than 44% at
3weeks.
We are able to show that for venous leg ulcers,
a simple rating system score based on size and
duration can give a good indication of the likely
outcome at 24 weeks. Falanga etal. incorporated
measurement of epithelial advancement into a
scoring system on the healing of venous leg
ulcers. This system [wound bed score] also examines other characteristics including the extent of
skin dermatitis around the wound, the presence
of eschar, callus, and/or brosis around a wound,
pink, or red wound bed, exudate, and the volume
of the edema (Table6.2).
The complexity of the wound is likely to exert a
signicant inuence on the progression of the healing process, and the factors that combine to deter-
6 The TIMEH Protocol
https://t.me/medicina_free
Table 6.2 Size of the wound ( WS: small, WM: medium, WL: large, WXL: extra large, WXXL: extra extra large)
SIZE– volume <50cm
W WS WM WL WXL WXXL
Score W 1 2 4 8 32
Table 6.3 Level of pain
Table pain Pain No=1 Little=2 Much=3
Table 6.4 Risk factors
1 Major 80years old 2
2 Lack of nutrition 2
3 Preparing diseases 2
4 Not self-sufcient 2
5 ASA– Anesthesiological risk index 3–4 2
3
50–100cm
GC: General condition of the patient
GC score calculation
Indicators NO=0/SI=2
3
100–200cm
3
200–300cm
3
>300cm
3
55
mine it can be classied into four main groups:
patient factors, factors related to the wound, knowledge of the HCP, factors, and resources related to
the treatment. In a study by Margolis etal. on a
group of patients with venous ulcers, it has emerged
a correlation between some specic characteristics
of the wound and the healing process: wound duration, size, and depth of the wound.
Ulcer size [>2cm2], the duration [>2months],
and depth [penetration through exposed tendon,
ligament, bone, or joint] were the three most
important factors for predicting the outcome.
Patients with all three factors had only a 22%
chance of healing by 20weeks (Table6.3).
For the physiological nature of the healing
process, it is inevitable that large wounds will
require more time to heal than smaller wounds. In
addition, the longer a wound remains open, the
greater the risk of complications, such as infections, is present.
Therefore, a treatment that reduces the size of
the wound and the infection risk is able to offer
potential benets. The presence of necrotic tissue
in a wound has been for a long time considered
an obstacle to the evaluation of the lesion, as well
as a potential predictive factor of delayed healing
and a possible outbreak of infection (Table6.4).
In chronic wounds, there is a tendency for the
inammatory response [which is an important
element of the initial response to the lesion]. This
results in increased production of proinammatory cytokines, reactive oxygen species,
and proteolytic enzymes [such as certain MMPs,
elastase, and plasmin].
This activity is combined with a minor issue,
for example, inhibitors TIMP (Table6.5), and is
further enhanced by alterations of pH at the level
of the wound bed. Excessive activity of these
enzymes causes not only deleterious extracellular
matrix destruction, but also inactivation of growth
factors. There is a correlation between the state of
chronic inammation of a wound, the high levels
of protease exudate, and the slowdown in the process of tissue repair.
The control of inammation and the concentration of MMPs (metalloproteases) are essential, as
the protease not only degrades the fabric, but also
leads to the growth factors activity’s reduction.
Gjødsbøl etal. found a signicant link between
diversity and the density of the bacterial species
detected on the diagnostic buffer and the time
required for wound healing. Also, the presence in
a wound of specic bacterial species has been put
in relation to the outcome of healing.
For example, the presence of Pseudomonas
aeruginosa in venous leg ulcers can delay healing. According to Mogford et al., an ischemic
wound is probably the most common cause of
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