Wound infection
Treating diabetic
lesions: a key ingredient is missing
Gérard V. Sunnen, MD, a New Yorkbased, internationally renowned ozone
therapist, looks at the treatment of diabetic wounds with medical ozone.
Diabetes is a disorder of
metabolism and of the circulation.
Chronic metabolic
irregularities linked to poor
circulatory perfusion and
nerve damage can affect a
number of organ systems,
including skin tissues. In this
article, the focus is on factors
in diabetes that can
contribute to dermal breakdown,
ulceration, and infection.
Most importantly, it
proposes a treatment
modality, which, backed by
solid experimental, and clinical
data accumulated worldwide,
shows great promise in
the management of diabetes related
skin lesions.
The conditions surveyed
include infected wounds,
skin ulcers and gangrene.
These wounds, in the
context of diabetes, are
notoriously difficult to
resolve. Healing resistance is
thus a well-recognised
element of frustration in
their clinical care.
In most of the above
conditions, multiple factors
play into healing resistance.
Among them are circulatory
impairments, neurological deficits, tissue injury, and
immunological compromise.
A central factor is the
proliferation of infectious
microorganisms that, by the
variety of their families,
their toxin-producing
capacities, and their resistance
to antibiotics, offer
daunting obstacles to standard
treatment regimens.
Approximately 15% of the
estimated 20 million
Americans afflicted with
diabetes mellitus develop
lower leg skin ulcers. Of
those patients, 20% will
eventually require amputations.
Diabetes mellitus is
the leading cause of nontraumatic lower extremity amputation in the
United States (LeRoith
2003).
Factors contributing to skin
lesions in diabetes:
- Circulatory impairment
Arteries and arterioles in
chronic diabetes are prone
to plaque buildup (Tesfaye
2005). The precise reason for
this phenomenon is still
elusive, yet it is well documented
that Type II noninsulin
dependent diabetes
is linked to abnormal blood
lipid profiles known as
diabetic dyslipidemia
(Goldberg 2004). Lowdensity
lipoproteins particles
are smaller in size and thus more apt to adhere to
vessel walls, resulting in
progressive vascular occlusion
(Beckman 2002; Renard
2004). Lowered oxygen and
nutrient supplies stress
tissue resilience and impair
recovery from injury
(Chapnick 1996).
- Neuropathy
Poorly controlled diabetes is
correlated with peripheral
nerve dysfunction. The
mechanisms of diabetic
injury to neurons are poorly
understood. Higher blood
glucose level seem to
promote oxidative stress in
neurons, but much more
complex mechanisms are implicated (Tomlinson 2002).
Diabetic neuropathy can involve
motor, sensory, and autonomic
system neurons. Sensory neuron
malfunction is translated as loss of
feeling, reflex loss, problems with
limb position sense, tingling (paresthesias)
and pain. Motor impairment
shows as muscle weakness.
Autonomic neuropathy alters local
circulation (Boulton 2004, Bensal
2006).
- Mechanical stress
Chronic and repeating pressure on
the skin compresses dermal arterioles,
inhibiting tissue perfusion. Tissue
weakness leads to ulceration. Ulcers
are fertile ground for pathogenic
microorganisms, and surrounding
tissues become prone to cellulitis. At
times, the ulcer crater reaches the
underlying bone, initiating
osteomyelitis (Boulton 2000).
- OZONE
The oxygen atom exists in nature in
several forms: (1) As a free atomic
particle, singlet oxygen (0), it is highly
reactive and unstable. (2) Oxygen
(02), its most common and stable
form, is colourless as a gas and pale
blue as a liquid. (3) Ozone (03), has a
molecular weight of 48, a density one
and a half times that of oxygen, and
contains a large excess of energy (03 g
3/2 02 + 143 KJ/mole). It has a bond
angle of 127° ± 3°, resonates among
several hybrid forms, is distinctly blue
as a gas, and dark blue as a solid. (4)
04, a very unstable, rare, nonmagnetic
pale blue gas readily breaks down into
two molecules of oxygen.
Ozone, as a triatomic configuration
of oxygen, possesses supreme
oxidising power derived from its
marked tropism for extracting electrons
from other molecules, simultaneously
releasing one of its own
oxygen atoms in the process.
- Ozone as a drug
Ozone’s capacity for inactivating
microorganisms has been increasingly
appreciated since the turn of the last
century (Viebahn 1999). In the past
few decades, ozone’s action against bacteria, viruses and fungi has sparked
keen interest for its use, not only for
purifying water supplies, but also for
medical objectives.
Ozone/oxygen mixtures exert
significant antimicrobial activity. As
with many medications, however,
ozone has a range of action that, in
the terminology of pharmacokinetics,
is referred to as a therapeutic window
(Bocci 2005). Indeed, ozone applied in
concentrations that are too low, has
little therapeutic effect. Applied externally
in high concentrations, ozone
may become irritating and tissuetoxic.
Due to ozone's demarcated therapeutic
range, ozone concentrations
administered to the patient need to be
carefully calibrated and controlled.
Optimally therapeutic ozone/oxygen
mixtures require state-of-the-art quantitative
(dosage, concentration), as
well as qualitative (purity) controls
currently available in contemporary
ozone generation technologies, all
predicated upon the evaluation of the
lesions under treatment.
- Ozone administration
Ozone is a gas with a half-life of
approximately one hour at room
temperature. Medical ozone generation
and delivery systems therefore
require that ozone be created at the
moment it is to be administered.
Ozone, in this sense is not a drug that
has a shelf life enabling it to be kept
for long periods of time.
Ozone is created by applying energy
to oxygen. The oxygen source should
be pure and devoid of nitrogen or
other impurities. The presence of too
much nitrogen favours the production
of tissue-toxic nitrogen oxides.
Importantly, the humidity level of
the ozone/oxygen mixture enters into
the treatment protocol. Indeed, in
certain wounds, humidity added to
the ozone/oxygen mixture, markedly
enhances therapeutic results.
- Ozone’s actions on pathogens
Bacteria fare poorly when exposed to
ozone, a fact appreciated since the
19th century (Viebahn 1999). Ozone
is a strong germicide needing only micrograms per litre for
measurable action. At a
concentration of 1 mg per
litre of water at 1°C, ozone
rapidly inactivates coliform
bacteria, staphylococcus
aureus, and Aeromonas
hydrophilia (Lohr 1984). The
inactivation rate for E. coli,
takes place in relatively
small concentrations of
ozone, and is influenced by
pH and temperature
(Ivanova 1983).
At dosage concentrations
used in external therapy,
ozone essentially inactivates
all bacterial species. This
holds true for oxygendependent
aerobic organisms,
for oxygen-independent
anaerobic bacteria
associated with gangrene,
and for facultative species
that can function with or
without oxygen. Spores and
cysts are neutralised as well
(Ishizaki 1986, Langlais
1986). Spores of Bacillus
cereus and Bacillus megaterium
are susceptible to
ozone exposure (Broadwater
1973). Ozone’s universal
antibacterial action makes it
an agent of choice in the
management of wound
infections colonised by
bacterial species belonging
to diverse groups.
An incomplete list of
bacterial families susceptible
to ozone inactivation includes
the Enterobacteriaceae, a
large group whose natural
habitat is the intestinal tract
of mammals. These Gramnegative
organisms include
Escherichia coli, Salmonella,
Enterobacter, Shigella,
Klebsiella, Serratia, and
Proteus. Other ozone-sensitive
bacterial species include
Streptococci, Staphylococci,
Legionella, Pseudomonas,
Yersinia, Campylobacteri,
and Mycobacteria (Dyas
1983, Broadwater 1973).
The cell envelopes of
bacteria are composed of
intricate multilayers.
Covering the bacterial cytoplasm
to form the innermost
layer of the envelope is
the cytoplasmic membrane,
made of phospholipids and
proteins. Next, a polymeric
layer built with giant peptidoglycan
molecules provides
bacteria with a stable architecture.
In Gram-positive
organisms, the pepticoglycan
shell is thick and
rigid. By contrast, Gramnegative
bacteria possess a
thin pepticoglycan lamella
on which is superimposed
an outer membrane made of
lipoproteins and
lipopolysaccharides. In acidfast
bacteria, such as
Mycobacterium, up to one
half of the capsule is formed
of complex lipids (Parish
2005, Hogg 2005).
The most cited explanation
for ozone's bactericidal
effects centres on disruption
of cell membrane integrity
through oxidation of its
phospholipids and lipoproteins.
There is evidence for
interaction with proteins as well (Mudd 1969). In one
study exploring the effect of
ozone on E. coli, evidence
was found for ozone's penetration
through the cell
membrane, breaking the
closed circular plasmid
DNA, which would presumably
diminish the efficiency
of bacterial procreation
(Ishizaki 1987).
- Fungi
Fungi are frequent inhabitants
of chronically infected
wounds. One study (Moussa
1999) found colonisation by
Candida and Aspergillus.
Fungal organisms neutralised
by ozone exposure include
Candida, Aspergillus,
Histoplasma, Actinomycoses,
and Cryptococcus. The
multilayered cell walls of
fungi, composed of carbohydrates,
proteins and glycoproteins,
contain many
disulfide bonds sensitive to
ozone oxidation.
- Protozoa
Protozoan organisms are
often found in chronically
infected wounds. Species
disrupted by ozone include Giardia, Cryptosporidium,
and free-living amoebas,
including Acanthamoeba,
Hartmonella, and Negleria.
Several authors have demonstrated
ozone’s capacity to
penetrate through the walls
of Giardia cysts causing fatal
structural damage (Widmer
2002, Wickramanayake 1984).
- Ozone’s cutaneous
physiological effects
Oxygen has long been established
as beneficial in many
pathological conditions,
forming the basis for the use
of hyperbaric oxygen treatment
for carbon monoxide
poisoning, decompression
sickness, gas gangrene and
stroke, among others.
Oxygen under pressure,
applied to infected tissues,
inhibits the proliferation of
anaerobic bacteria and stimulates
local circulation
(Wunderlich 2000).
Ozone, when added to
oxygen, however, has properties
that clearly transcend
oxygen administration
alone. The two properties
invoked are:
1. Ozone’s extremely broad
range of antipathogenic
action and,
2. The vasodilation of arterioles
promoting tissue
oxygenation and the
delivery of nutrients and
immunological factors to
compromised tissues; and
the vasodilation of veins,
increasing venous
outflow and the removal
of toxins.
Diabetic skin conditions
benefited by ozone therapy:
- Wounds with a potential
for infection
This category addresses
wounds that are not yet
infected but have a high
probability for eventual infection.
Post-surgical wounds, injuries such as abrasions,
contusions and lacerations
are salient examples.
The use of topical ozone
therapy in these cases may
be solely preventive, aimed
at inhibiting the proliferation
of potentially infective
organisms. Preventative
topical ozone therapy may
thus stave off the development
of potentially disastrous
infectious complications.
- Poorly healing wounds
Wounds healing in an indolent
manner are apt to
regress if treatment continuity
is interrupted.
In these wounds, anaerobic
bacteria – bacteria that
do not need oxygen for
their growth (e.g., Bacteroides, Clostridium) –
may be active at deeper
levels of the dermis, insulated
from the influence of
oxygen. While anaerobic
bacteria are responsible for
many devastating infections
including gas gangrene,
aerobic bacteria normally
found on skin surfaces such
as Staphylococcus epidermis,
Corynebacteria, and
Propionobacteria, given
propitious circumstances,
are capable of remarkably
aggressive infectivity.
- Diabetic leg ulcers
Diabetic ulceration is accelerated
by poor circulation
and neuropathy. One study
(Anandi 2004) reported
bacterial culture results for
107 patients with diabetic
foot lesions. They included
E. coli, Klebsiella, Pseudomonas,
Proteus, Enterobacter,
Clostridium perfringens,
Bacteroides, Prevotella, and
Peptostreptococcus.
The treatment of diabetic
ulcers requires a multidisciplinary
approach, including surgical, topical, and
systemic interventions
when indicated (Cavanagh
2005, Kruse 2006). Topical
antibiotics often fail to
penetrate far enough into
the wound and frequently
cause secondary dermatitis
and allergy in their own
right (De Groot 1994). For
this reason, they are not
generally recommended.
Systemic antibiotics,
prescribed for infections
transgressing ulcer borders,
can only address a portion
of the spectrum of microorganisms
cultured from such
wounds. Bacterial resistance
is common (e.g., ß-lactam
antibiotic resistance, as in
methicillin-resistant staphylococcus).
Ozone applications in
diabetic ulcers provide
essential dual functions of
topical broad-spectrum
coverage and circulatory
stimulation. In addition,
ozone, via multiple serial
applications and higher
dose ranges, is able to
further its penetration into
deeper tissue layers where
anaerobic bacteria are apt to
reside.
- Gangrene
Gas gangrene, also known
as necrotising fascitis,
myositis, and myonecrosis
is feared because of its rapid
evolution leading to the
galloping breakdown of
affected tissues (Chapnick
1996, Falanga 2002)).
Several bacterial species are
implicated in this process,
the most common being
Clostridium and toxinproducing
Group A
Streptococcus families. Other
bacterial species implicated
in gas gangrene include E.
coli, Proteus, Staphylococcus,
Vibrio, Bacteriodes, and
Fusiforms (Caballero 1998). Gas gangrene may become a
fatal complication of diabetic
and decubitus ulcers.
Anaerobic and facultative
bacteria feed on sugars and
glycogen, produce lactic
acid, and gases such as
methane, carbon dioxide,
and hydrogen. Their life
threatening toxins cause
severe tissue breakdown, hemolysis, renal failure,
and shock.
These impressively
destructive wounds demand
emergency ozone application
as an important
adjunct to their multidisciplinary
interventions.
The practice of external
ozone therapy in diabetic
skin lesions
In every case, an individual
assessment has to be made
relative to the skin lesion
under treatment. Noted in
this evaluation are the size
(diameter and depth) of the
lesion, and in deeper
lesions, the involvement of
dermal tissues, ligaments,
muscle and bone. Also, the
presence of purulence and
necrosis, the relative health
of surrounding tissues, and
adjacent circulatory competence.
Ozone therapy is always individualised to incorporate
these clinical observations.
Accordingly, ozone
concentrations are adjusted,
as are lengths and frequencies
of treatment, all recalibrated
as treatment
progresses.
In the practice of external
ozone application, a
specially designed ozoneresistant
envelope is used to
enclose the area being
treated. A precise fitting of
the envelope is needed in
order to ensure a constant
ozone/oxygen concentration
within the envelope milieu and a proper containment
of the gas. Ozone will
thus be prevented from
escaping into the ambient
environment, reducing
respiratory exposure to
treating personnel.
The ozone concentrations
prescribed during the
course of treatment, the
duration and frequency of
individual sessions, and the
lengths of the overall
course of therapy are all
predicated upon the evolution
of the specific medical
condition under treatment.
In extensive wet ulcers and
burns, for example, initial
topical ozone concentrations
need to be low in
order to prevent excessive
systemic ozone absorption.
With gradual epitheliasation
of the ulcer wound, applied ozone concentrations
will require corresponding
adjustments.
Advantages of topical ozone
therapy in diabetes
1. The ease of administration
of this therapy.
Once the principles of
ozone dynamics and the
art of adapting ozone
dosages and treatment
protocols are mastered
by the clinician, topical
oxygen/ozone therapy
can safely be applied to
a broad range of
diabetes-related afflictions.
2. Ozone is an effective
antagonist to an enormous
range of pathogenic
organisms. In this
regard, ozone cannot be
equaled. It inactivates
aerobic, facultative, and
anaerobic bacterial
organisms, a wide spectrum
of viruses, and a
comprehensive range of
fungal and protozoan
pathogens. To replicate
this therapeutic action,
ulcerative conditions
would have to be treated
with an assortment of
various systemic antibiotic
agents. In the
context of accepted
contemporary medical
practice, this is not
feasible.
3. External ozone therapy,
applied in a timely
fashion, may obviate the
need for systemic antipathogen therapy,
thus saving the patient
from all the side effects
and organ stresses this
option entails. External
ozone is both a preventive,
acute care, and
chronic care therapeutic
agent.
4. External ozone application
to superficial tissues whose blood supply is
reduced enhances tissue
blood and oxygen perfusion.
5. There is evidence that
ozone, via its oxidising
properties, inactivates
bacterial toxins. Toxins,
whose function is to
destroy tissues, provide
bacteria with colonising
advantage.
6. Ozone exerts its anti panpathogenic
actions
through entirely different
mechanisms than
conventional antibiotic
agents. The latter must
be constantly upgraded
to surmount pathogen
resistance and mutational
change. Ozone,
on the other hand, presents
a direct and
powerful oxidative challenge
that any and all
pathogens are incapable
of circumventing.
7. Externally applied
ozone/oxygen mixtures
are entirely compatible
with systemically
administered antibiotics,
as they are with debridement and other
local wound care procedures.
Disadvantages of topical
ozone therapy in diabetes
1. Ozone/oxygen mixtures
are not transportable
and need to be created at
the site and time of
administration.
2. Ozone/oxygen mixtures
need to be administered
serially in diabetic
wounds. This may translate,
in many circumstances,
to daily applications
until the lesion
resolves.
3. Ozone/oxygen mixtures,
applied externally, have
limited penetrability.
While they possess panpathogenic power on
ulcer surfaces, their therapeutic
action has limited
range at greater depths of
ulcer boundaries.
Conclusions
Topical ozone/oxygen
therapy has shown effectiveness
and safety in healing
diabetic skin afflictions. In
this article, the following
are cited: Wounds with
potential for infection,
infected wounds, poorly
healing wounds, diabetic leg
ulcers, decubitus ulcers and
gangrene.
Ozone possesses unique physico-chemical attributes
enabling it to exert potent
antipathogenic activity.
Applied to the adjunctive treatment and management
of diabetic leg lesions, ozone
can tip the balance from
chronic failure to resolution.
There is one crucial
element missing from
contemporary therapeutic
regimens for diabetic skin
lesions: Ozone
Dr Gerard Sunnen is the CEO
of Ozonics International New York –
www.ozonicsint.com
He has written several papers
on the medical use of ozone
including “Ozone in medicine:
overview and future
directions” – first published
in the Journal
Advancement in Medicine
1988.
