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The Role of Iodine in Antisepsis and Wound Management: A Reappraisal

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Review article
Acta chir belg, 2003, 103, 241-247

The Role of Iodine in Antisepsis and Wound Management : A Reappraisal

G. Selvaggi, S. Monstrey, K. Van Landuyt, M. Hamdi, Ph. Blondeel
Plastic Surgery Department, Gent University Hospital, Gent, Belgium.

Key words. Iodine ; povidone-iodine ; wound healing ; antisepsis.

Abstract. For more than 150 years, iodine has been used for the prevention of infection and for the treatment of wounds.
Nowadays a large amount of published evidence is available and, although it is generally in support of the use of iodine
product, it is confused by being a mixture of laboratory, animals and human studies, often using different preparations.
This makes interpretation and comparison difficult.
After new developments and publications, the role of iodine in antisepsis and in wound management needs to be reeval-
uated.
We mainly focused our review on the following problems : the role of the newly developed formulations of iodine prepa-
rations, its antimicrobial activity, the possibility of impairing the wound healing process, the role of iodine in the prob-
lem of growing resistance against antibiotics and antiseptics.
New formulations seem to keep the same clinical efficacy, avoiding the problem of toxicity ; it seems that the antibac-
terial activity of iodine is superior compared to other products and, in contrast with antibiotics and other antiseptics, it
seems to have no resistance problem.
It seems that povidone-iodine has all the characteristics to become the first choice antiseptic in wound treatment.

Introduction At that time, iodine was widely used as a particular

For more than 150 years, iodine has been used for the
prevention of infection and for the treatment of wounds.
Use of its beneficial impact had even existed much
earlier without any actual awareness of the active sub-
stance. Already in the Greek Age (4th century BC),
Theophrastus, Aristotle’s pupil and first expert in medi-
cal plants, described the use of seaweeds and other
plants in refreshing and relieving pain after sun burn
wounds.
During Napoleon’s Egyptian campaign (1798-1801),
wounded soldiers were treated with extracts from sea-
weeds and other plants enriched with iodine at high con-
centrations from sea water (1). Also during the
American Civil War (1863), the use of iodine for disin-
fections was widespread (2).
Even if iodine-containing plants were well used
before, the natural element iodine was only discovered
in 1811 by the Dijon chemist Bernard Courtois. It was
given its name from the Greek ioeides meaning “violet
coloured”, because of the intensely violet colour of its
vapours (1).
Iodine’s bactericidal efficacy was first described sci-
entifically by DAVAINE (3) in 1880 and it was only
between the 19th and 20th century that surgeons started
to use iodine as a preoperative disinfectant.
iodine compound, called iodoform (triiodomethane,
CHI3) and as ethylic iodine tincture with all the disad-
vantages of lacking stability and highly aggressive
action on skin and mucosa (1).
Already in 1919 Alexander Fleming stated that, in
considering and estimating the value of an antiseptic it
was probably more important to study the effect on tis-
sues than on bacteria (4).
It was the development of the iodophors (substances
that can carry Iodium, e.g. povidone-iodine), and the
detoxification of iodine by binding it to macromolecules
by SCHELANSKI (5), which made the large-scale use of
this highly effective microbiocidal possible.
Despite a history spanning almost two centuries, a lot
of old and new questions about the role of iodine still
remain unanswered :
1. What is the role of the newly developed formulations
of iodine preparations ?
2. How exactly do iodine-containing agents compare to
the other antiseptics available nowadays in their
antimicrobial activity ?
3. To what degree is iodine deleterious to normal living
cells and does it impair the wound healing process ?
4. How does the problem of growing resistance against
antibiotics affect the use of antiseptics in general and
specifically of iodine-containing agents ?
242
5. Are there specific situations in which PVP-I should
better not be used or is even contraindicated ?
The purpose of this article is to review the recent litera-
ture concerning iodine-containing agents in order to
answer the above-mentioned questions.
New developments and publications require that the
role of iodine nowadays in antisepsis and in wound man-
agement needs to be reevaluated and redefined !
Discussion
1. Iodine formulations
Elemental iodine is a violet-black non-metallic crys-
talline solid, with an atomic weight of 126.904, which
readily sublimes to form a pungent irritating violet
vapour. Its solubility in water is only 1:3000.
Iodine, fluorine, chlorine, bromine comprise a group
of elements called the halogens (from the Greek : salt
formers). Iodine salts are widely distributed (sea water,
fish, oysters and certain seaweeds). Commercially,
iodine used to be obtained by burning seaweed (kelp),
but it now comes mostly from Chile saltpetre, which
contains small quantities of sodium iodate (6).
Iodine is an essential nutrient required for synthesis
of thyroid hormones and the body requires 100-200µg
iodine per day (6).
Iodine compounds have diverse uses : potassium
iodate and sodium iodide are used to treat iodine defi-
ciency diseases, other iodine salts are used in expecto-
rants and as diuretics (7).
Iodine has traditionally been available in Solution
2%, Tincture 2%, Strong Solution 5% and Strong
Tincture 7%.
It has been demonstrated that, with these old formu-
lations and in a normal solution at least seven iodine
forms are present in a complex equilibrium with molec-
ular iodine (I2), which is primarly responsible for the
antimicrobial efficacy (8).
This resulted in a high degree of instability of these
solutions.
These problems were overcome by the development
of “iodophors” (iodine carriers or iodine releasing
agents).
Iodophors are complexes of iodine and a solubilizing
agent or carrier, which acts as a reservoir of the active
“free” iodine (8).
The two most important iodophors used nowadays
are povidone-iodine and cadexomer-iodine.
1) Povidone-iodine.
Povidone-iodine (Polyvinil-Pyrrolidone-Iodine or PPI
complex) is an iodophor containing a loose combination
of iodine with a non-ionic surfactant in which some of
the iodine may be available in its molecular form. The
G. Selvaggi et al.
antibacterial activity of such iodine is identical to that of
iodine dissolved in ethanol or solubilised in potassium
iodide.
The iodine in povidone-iodine has virtually no vapor
pressure hence no iodine loss occurs and there is no sig-
nificant odor (9).
It stains the skin and clothing less than iodine solu-
tions and is also less irritant under occlusive dressing,
which simply reflects that there is less free iodine. The
brown color imparted to the skin, fabrics and during its
use can be readily removed (9), but loss of the brown
color from povidone-iodine is always associated with
loss of antibacterial properties (10).
Some 30 years after the synthesis of povidone-iodine,
a paradox in the behaviour of 10% solutions was report-
ed : its antibacterial action increased with the degree of
dilution (low concentrations, i.e. 0.1% to 1%, were more
rapidly bactericidal than a full-strength, i.e. 10%, solu-
tion) (11). This effect, which is maximal between 1:10
and 1:100 dilutions, has been fully described, together
with observations on povidone-iodine’s mechanism of
action. One hypothesis is that the concentration of “free”
iodine significantly contributes to the bactericidal acti-
vity of povidone-iodine solution : dilution of povidone-
iodine results in weakening of the iodine linkage to the
carrier polymer with a concomitant increase in the
amount of elemental (free) iodine in solution (11, 12).
Polyvinil-pyrrolidone-iodine newer vehicles include
PVP-I Solution, PVP-I Ointment, PVP-I Cream (13) and
PVP-I Gel Alcohol (14).
In particular, PVP-I Gel Alcohol (this product does
not exist in Belgium, while a PVP-I Hydroalcoholic
solution is available) delivers rapid and persistent activ-
ity against a broad spectrum of bacteria as a skin prepa-
ration formulation : within 30 sec., all challenge
microorganisms were reduced below detection level,
while Betadine PVP-I Solution needed 5 minutes ; PVP-
I Gel Alcohol also showed a long-lasting effect up to 24
hours (14), while PVP-I showed a duration of action of
about 14 hours (15).
A more methodic investigation reported a different
bactericidal kinetic of PVP-I dermal solution, showing a
significant reduction of aerobic and aero-anaerobic bac-
teria even after 15 seconds (16).
CALFEE found no significant difference in skin disin-
fection among 10% PVP-I, 70% isopropyl alcohol, tinc-
ture of iodine and PVP-I with 70% ethyl alcohol (Persist),
although there was some evidence suggesting greater effi-
cacy among the alcohol-containing antiseptics (17).
This was confirmed in another study by ARATA et
al. (18).
Wiping aqueous PVP-I 10% off after 30 seconds of
application did not show a significant difference in the
reduction from baseline counts of skin flora at 5, 30, 60
and 120 min (19).
The Role of Iodine in Antisepsis
Antiseptics and activity against micro-organisms
Anti-septics Speciality G+
Alcohol Ethanol 70° XX
Iodium-derivates Iso-Betadine XXX
Acetic acids Crystacide X X
Chlorumderivates Dakin Cooper XXX
Chlorhexidine Hibitane XXX
Quat. Amonium Cetavlon XX
Hexamidine Hexomedine X X
Hexetidine Hextril X X/O
2) Cadexomer iodine
Around 15 years ago, another iodine complex iodophor,
cadexomer iodine, became available ; this is a polysac-
charide, a three-dimensional starch lattice containing
0.9% iodine. Cadexomer iodine has a high absorptive
capacity. When fluid is absorbed, iodine is slowly
released. It is suggested that this permits maintenance of
more constant and prolonged iodine levels in the wound
bed whereas other forms of iodine are broken down
more rapidly.
However, there seems to be no information concern-
ing either the rate of release of iodine from cadexomer
iodine or the extent to which this iodine permeates
beyond its carrier. Cadexomer iodine is a purpose-
designed wound dressing ; being insoluble, it is unlikely
to have other applications (20).
In conclusion, the development of new formulations,
such as iodophors, has resulted in a major break-through
in the use of iodine containing agents : toxicity has been
eliminated, the formulations are more stable and despite
a lesser concentration of iodine, the same high level of
clinical efficacy is maintained (13, 20).
2. Antiseptics properties
As a general rule, less is known about the mode of action
of antiseptic agents compared to antibiotics. Antiseptic
agents usually have a broader spectrum of activity than
antibiotics and, while the latter group tends to have spe-
cific intracellular targets, the former group may have
multiple targets (7).
Although the precise mechanism of iodine has not
been completely determined, it has been suggested that
the lethal effect of iodine on microorganisms can be
explained as follows : iodine rapidly penetrates the cell
wall and proceeds to dislocate protein synthesis, it
disrupts the function of respiratory chain enzymes
and interferes with lipid membrane and nucleic acid
function through several diverse mechanisms of
action (7, 21).
Less is known about the antiviral action of iodine, but
it has been demonstrated that nonlipid viruses and par-
voviruses are less sensitive than lipid enveloped virus-
243
Table I
G- CNM Spores Fungi Virus
XX XX O X +/-
XXX XXX XXX XXX XX
O O X X
XXX XX XX XX XX
XX O O X X
X O O X O
O O X O
O O X O
es (22). Similarly to bacteria, it is likely that iodine
attacks the surface proteins of enveloped viruses, but
they may also destabilize membrane fatty acids by react-
ing with unsatured carbon bonds (23).
Concerning iodophors, they are considered to be less
active against certain fungi and spores than tinctures,
although the germicidal activity is maintained (24).
Antimicrobial activity of antiseptics can be influ-
enced by many factors such as formulation effects, pres-
ence of an organic load, synergy, temperature, dilution,
and test method (24, 25).
More than 100 articles have been written specifically
about iodine and its antiseptic activity, comparing it to
other antiseptics and antibiotics.
The whole literature, a mixture of laboratory, animals
and human studies, using a considerable number of dif-
ferent preparations at different concentrations, is stating
without doubt the superiority of iodine, in topical anti-
sepsis, compared to other substances.
Iodine has been shown to be the only agent that is
simultaneously active against gram+, gram-, spores,
amoebic cysts, fungi, protozoa and yeasts (26, 27), and
MRSA, while other antiseptic agents, as chlorhexidine,
never achieved a total kill against all the strains tested
(both in clinical and laboratory conditions) (28-30).
In particular, GOLDENHEIM confirmed the high degree
of effectiveness of PVP-I solution (10%) and cream
(5%), compared to chlorhexidine, against MRSA in
vitro (28). MCLURE had the same results on 33 clinical
isolates of MRSA, against which chlorhexidine never
achieved a total kill, and only killed three out of 33
strains (9% success), while PVP-I achieved full efficacy
against all of them (100% success) (29).
These results are summerized in the Table I (31).
The time interval in antiseptics is also important :
PVP-I showed high bactericidal activity against com-
mon bacteria after only 30 seconds of exposure (32).
After PVP-I application, the time required by skin bac-
teria to return to usual concentration on the skin is about
6 to 8 hours (25).
In conclusion, there is almost a universal agreement
in the literature that the overall antibacterial activity of
PVP-I is superior compared to other products.
244
3. Effect on the wound healing process
It is a common belief that, the stronger the bactericide
effect of an antiseptic agent, the more deleterious is its
effect on living tissue.
Probably because of this belief, many surgeons and
general practicioners have long been convinced that
iodine preparations, because of their extreme bacterici-
dal effect, did not really promote good wound healing.
Indeed, older studies and preparations have shown
impaired wound healing and reduced wound strength
with the use of iodine (33, 34).
However, newer literature has demonstrated that
many of those older studies confused different study
conditions : animal versus human research, in vivo ver-
sus in vitro conditions and differences in preparations of
iodine at different concentrations.
The recent literature has demonstrated that the con-
clusions of those older studies are not always reliable
and comparable (35).
Very recent articles seem to go even a step further,
demonstrating not only the absence of a deleterious
effect on the wound healing process, but also indicating
the presence of a beneficial effect, based on a molucular
explanation.
Nowadays, new formulations seem to have reached a
great improvement (not jeopardizing proliferation of
fibroblasts and epithelial cells, neither collagen produc-
tion) in wound healing, if compared to the old iodine
containing agents (13).
MAYER, in his review focused on in vivo and human
studies, affirmed that newer vehicles, such as PVP-I
ointment and cream, might actually enhance the healing
process, especially when PVP-I ointment is used in con-
junction with the newer gel-type occlusive dres-
sings (13).
Data from MOORE (36) proposed a mechanism addi-
tional to iodine anti-bacterial activity in wound healing.
He demonstrated that the delivery of iodine to non-
actived macrophages within the chronic wound may
induce TNFa as a primary event. As a consequence,
iodine induces a fresh influx of macrophages and T-
helper cells, which are considered to play a positive role
in modulating wound healing (36).
BENNET, in 2001, proved that PVP-I significantly
enhanced angiogenesis (37).
Very recently, FUMAL showed how PVP-I increased
significantly the healing rate and reduced the healing
time by 2-9 weeks ; histologically, PVP-I applications
did not alter the microvessels and did not significantly
reduce the density in dendrocytes and fibroblasts (while
other two agents tested, silver sulfadiazine and chlorhex-
idine digluconate, appeared to alter the superficial
microvasculature inclunding the dendrocyte population)
(38).
G. Selvaggi et al.
SCHMIDT reported a possible additional mechanism :
cadexomer iodine formulations may modulate the redox
environment of wounds and hence contribute beneficial-
ly to wound healing (39).
Finally, GILCHRIST in ’97 wrote an important report of
a consensus meeting on the use of iodine in wound care :
the overall impression was that the product (especially
cadexomer iodine) does have a role in enhancing healing
in chronic wounds (35).
In conclusion, the literature seems to have moved
away from earlier criticism of iodine with reports of
deleterious effect of iodine on the wound healing
process, towards a much more positive attitude with an
even beneficial stimulating effect on wound healing.
4. The growing problem of resistance
Nowadays, the growing resistance against antibiotics
(and antiseptics ?) has become a worldwide and increas-
ing problem (21).
In recent years, considerable progress has been made
in understanding more fully the response of different
types of bacteria (mycobacteria, nonsporulating bacte-
ria, and bacterial spores) to antibacterial agents.
The widespread use of antiseptics and disinfectant
products has prompted some speculation on the devel-
opment of microbial resistance, against antibiotics, anti-
septics and disinfectants and in particular on the occur-
rence of cross-resistance among all these products (24,
25).
The ways whereby bacteria circumvent drug action
are many and varied, ranging from intrinsic imperme-
ability to acquired resistance (involving plasmids, trans-
posons and mutations). Resistance against antibiotics
may be explained by the inability to reach susceptible
target sites, they may be enzymatically inactivated, mod-
ified or expelled or mutations may arise such as to ren-
der the target sites insusceptible (40).
Mechanisms of bacterial resistance to biocides are
less well understood but cellular impermeability is a
major factor (40).
The problem of the cross-resistance between antisep-
tics and disinfectants and antibiotics has been ques-
tioned (31).
Some biocides have the ability to select for antibiotic
resistant mutants and vice versa (41).
An association between resistance to antibiotics and
biocides in Gram-negative bacteria has been observed
(40).
For Gordon (21), the possibility of an association
between multiple-antibiotic resistance and antiseptic
resistance exists : multiresistant strains of S. aureus
(including MRSA) possess the pSK1 family of multi-
resistant plasmids which variously encode resistance to
both antibiotics and antiseptics including chlorhexidine.
The Role of Iodine in Antisepsis
Table II
Descending order of resistance to antiseptics
and disinfectants
Prions
Coccidia
Spores
Mycobacteria
Cysts
Small non-enveloped virus (polio-virus)
Trophozoites
Gram-negative bacteria (non sporulating) (Pseudomonas)
Fungi
Large non-enveloped viruses
Gram positive bacteria (S. Aureus)
Lipid enveloped virus (HIV, HBV)
Extensive and prolonged use of chlorhexidine might
even promote the evolution and dissemination of multi-
ple-antibiotic resistance in S. aureus and other hospital
pathogens. He concluded stating that it might be prudent
to restrict the widespread use of chlorhexidine in the
hospital environment to preserve not only the useful life
of this antiseptic agent but also the value of many antibi-
otics (21).
For other authors, the problem of cross-resistance is
not that relevant, compared to the normal antibiotic
resistance (42) ; anyway, further studies are indicated.
KUNISADA demonstrated experimentally the acquisi-
tion of resistance of clinical isolated strains against com-
monly used antiseptics (chlorhexidine and alkyl-
diaminoethylglycine hydrochloride) ; strains that
acquired resistance against one antiseptic agent showed
also cross-resistance to all antiseptics except for PVP-I
(32).
This absence of acquired resistance after a long-term
use of PVP-I is also confirmed in other studies (43).
Table II shows the descending order of resistance of
different pathogenic species to antiseptics and disinfec-
tants (31).
Given that iodine containing antiseptic agents have
been in extensive clinical use in hospital for over 150
years without development of resistance, it is tempting
to hypothesize that it is the actual mechanism of action
of iodine, which stops the evolution of resistance : these
various iodine-directed mechanisms of action occur with
such speed at different and dispersed target sites that
even with the genetic versatility of S. aureus they prove
indefensible and rapidly lethal. Perhaps the most proba-
ble defense mechanisms that might evolve would be the
excretion of inactivating compounds or novel perme-
ability resistance, but even these have an extreme low
probability of evolution (21).
The clinical significance of MRSA, its treatment,
control policy and the importance of using PVP-I, have
been illustrated by Gordon (21) : in the UK about 15%
245
of all reported bacteraemias are caused by S. aureus with
a treated mortality of around 30%. S. aureus is also a
major nosocomial pathogen and its infections may jeop-
ardize the success of surgery.
Few works report the resistance of MRSA to iodine
formulations, but these studies considered very specific
situations (such as very long conservation period and
unusual storage ‘s temperature, and no in-vivo test was
used) (44-46).
In view of all these recent developments, it seems
logic to conclude that a growing resistance against anti-
septics and antibiotics in general should result in a grow-
ing use of iodine containing antiseptic agents (21).
5. Contraindications
Adverse effects of povidone-iodine have been rarely
published in the literature and only in sporadic case
reports.
These side effects include : reversible kidney failure
(47), convulsions with central nervous system involve-
ment (48), peritonitis after mediastinal lavage with PVP-
I (49).
There have also been reports on the disturbances on
thyroid function tests with no clinical signs in premature
infants after extensive use of PVP-I-containing com-
pounds (50), but there was no correlation between their
use and neonatal thyroid dysfunctions in controlled tri-
als (51).
A metabolic acidosis and fatal kidney failure has also
been reported in an extensively burnt patient : it was
attributed to the prolonged use of PVP-I over a large
Total Body Surface Area, but in this case the simultane-
ous sepsis and the deteriorating general condition of the
patient should be considered (52).
Irritative contact dermatitis (53) and acute allergic
reactions (54) caused by PVP-I have been reported.
Epicutaneous testing revealed hypersensitivity against
PVP-I in less than 1% of 6000 tested patients (55), while
other authors never noted allergy towards povidone-
iodine during many years of use (56).
It should be stressed that all publications on adverse
effects or possible contraindications for povidone-iodine
are sporadic case reports often with a questionable clin-
ical relevance.
Conclusion
For more than 2000 years, iodine-containing plants
(first) and iodine extracts and preparations (later) have
been used for the prevention of infection and the treat-
ment of wounds.
A large amount of published evidence is actually
available and, although it is generally in support of the
use of iodine product, it is confused by being a mixture
246
of laboratory, animals and human studies, often using
not always reliable and/or comparable methods, or using
a considerable number of different preparations. This
makes interpretation and comparison difficult. It is fur-
ther complicated by the lack of good controls and the
absence in many case of appropriate bacteriological
investigation (4, 36).
The purpose of this literature study is to review
specifically the recent literature and the new develop-
ments concerning iodine-containing agents.
In answer to the four key questions mentioned in the
introduction, the following conclusion can be drawn out
of the recent literature :
1. The availability of newer iodine-containing for-
mulations has stimulated a new interest on these prod-
ucts : these formulations, despite a lower concentration
of iodine, keep the same clinical efficacy, avoiding the
problem of toxicity (13, 20).
2. As to the bactericidal activity, few, if any, alterna-
tive antiseptics have such ubiquitous clinical applica-
tions as iodine-derivated products. There seems to be an
almost universal agreement in the literature that the
antibacterial activity of PVP-I is superior compared to
other products.
In most of the studies, it proved to be superior to
chlorhexidine and to other antiseptics in assessments of
disinfection performance against MRSA, fungi and
viruses, being the only one able to eradicate spores (26,
31).
3. It was a common belief, due to some old studies,
that iodine preparations could be deleterious to the
wound healing process.
Many of the concerns about iodine are based on the
toxicity against different cells (epithelial cells and
fibroblasts, immunitary system cells and endothelial
cells) of older formulations containing elemental iodine
or arise from in vitro studies, which may not necessari-
ly be relevant to in vivo situation.
The advent of povidone-iodine overcame the prob-
lems of irritancy associated with other iodine prepara-
tions when used on raw surfaces.
Newer preparations appear to be safe, still maintain-
ing the same antimicrobial properties (36).
Moreover, the possibility that iodine may have bene-
ficial effects on wound healing (by modulating the
secretion of cytokines) independent of any antimicrobial
activity has generated much interest and a new avenue
for research (36, 39).
4. In contrast with antibiotics and other antiseptics,
povidone-iodine seems to have no real resistance prob-
lem.
However, several authors concluded that the problem
of growing resistance against other antiseptics and
G. Selvaggi et al.
antibiotics (21) and the existence of cross-resistance
among these (24, 25, 40), with the exception of PVP-I,
should turn us to use more and more iodine preparations
(21, 31, 43).
5. As other authors (57), we agree that caution is
advised against extensive use of PVP-I in neonates due
to the increased permeability of their skin, also in burned
patients with very extensive burn injuries, and in indi-
viduals with known thyroid or renal dysfunction. A reg-
ular check-up of the thyroid function and renal function
can let the physicians to avoid the mentioned problems.
After reviewing the literature, we can reply to the
above-mentioned questions, and maybe we can redefine
the role of iodine nowadays in antisepsis and in wound
management : it seems that PVP-I has all the character-
istics to become the first choice antiseptic in wound
treatment.
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Stan J. Monstrey, M.D., Ph.D.
Plastic Surgery Department
Gent University Hospital
185 De Pintelaan
B-9000, Gent, Belgium
Tel : +32 9 240 32 27
Fax : +32 9 240 38 99
E-mail : stan.monstrey@rug.ac.be