Note: Descriptions are shown in the official language in which they were submitted.
CA 02395584 2002-08-09
1468-2
A Method and a Laser Device for Treatment
of Endo-Cavital Infections.
This invention relates to a method and an apparatus
for the treatment of endo-cavital infections, particularly,
abscesses such as cavernous tuberculosis, post-surgical intra-
abdominal abscesses and similar medical conditions. More
specifically, this invention relates to a system which allows
the simultaneous drainage of an endo-cavital space and
irradiation of an infected locus with laser-generated
ultraviolet light.
The use of ultraviolet light is a known and proven
technique in procedures for sterilising liquids and for
rendering drinking water safe for public consumption. For
these purposes, short wavelength, spectrally non-selective
ultraviolet light is used having a wavelength of from about
200nm to about 350nm. Within the so-called UV-C wave length
range (200-270nm), ultraviolet light is most effective in
destroying the microorganisms commonly found in untreated
water. Typical procedures are described by Dunn et al. in US
5,900,211; by Nesathurai in US 4,983,307; and by Wang et al. in
US 5,236,595.
It is generally accepted that microorganisms can be
broadly grouped into five basic families; these are bacteria,
viruses, fungi, protozoa and algae. These five families have
different properties, occur in different habitats and respond
differently to microbiocides such as antibiotics. Bacteria,
fungi, protozoa and algae are generally characterised as
comprising a cell wall, a cytoplasmic membrane and genetic
material which is essentially DNA material. Viruses are
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somewhat different and generally have an outer coating of
proteins surrounding genetic material which again is DNA
material. When harsh ultraviolet light penetrates the
microorganism, it causes disruption of chemical bonds within
the DNA system thus preventing the DNA replication step
required for reproduction of the microorganism. If a
microorganism cannot reproduce itself, it is effectively dead.
However, the cells of different microorganisms are
not the same: different microorganisms have different
sensitivities to different wavelengths of light within the UV
range; also the dose the UV light required to effect
microorganism destruction varies for different microorganisms.
The dose (or accumulated energy) is a product of the time for
which the microorganism is exposed to the radiation, and the
radiation power; most commonly, power is measured in Watts (W),
and time is measured in seconds.
TABLE 1. Average lethal dose densities for different
microorganisms(in mWsec/cm~) measured under a non-
selective UV irradiation (a Xenon lamp with a W band
filter centered at 254 nm).
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Microorganism Dose/cm2 Microorganism Dose/cm2
Bacillus anthracis 8.8 Dysentary bacilli 4.2
Shigella dysentariae 4.3 Escherichia coli 7.0
Shigella flexneri 3.4 Streptococcus 10.0
faecalis
Corynbacterium Staphylococcus 5.8
6.5 epidermis
diphtheriae
Vibri commo 6.5 Bacteriophage 6.5
(cholera) (E.coli)
Hepatitis 8.0 Salmonella 10.0
Influenza 6.6 Baker's yeast 8.8
Z,egionella 3.8 Mycobacterium 10.0
pneumophilia tuberculosis
Salmonella paratyphi 6.1 Polio virus 7.0
Salmonella typhosa 7.0
Table 1 shows that for different microorganisms, the
measured lethal dose (in vitro) is not constant.
In addition to using UV light to sterilise fluids
such as drinking water, lasers generating spectrally narrow-
line light in ranges other than in the UV range have also had
some use in medical therapy. In this context, it is relevant
to distinguish between the use of non-UV lasers for surgical
and other techniques and the use of W light to treat
microorganism infections. For example, in some therapeutic
procedures, He-Ne or Nd-YAG lasers are used as localised heat
sources, which stimulate blood supply and heat or destroy
selected tissues; these laser radiation wavelengths are
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generally in the red or near infrared ranges. Any
microorganisms present will only be affected by the laser
irradiation if the heat generated by the laser causes the
temperature of the microorganism to reach or exceed about 40°C.
Although temperatures in this range are lethal to many
microorganisms, the use of such lasers as a therapeutic tool to
control microorganisms is circumscribed by the unacceptable
damage this level of temperature can cause to surrounding
tissues.
Treatments of destructive forms of endo-cavital
infections, such as tuberculosis and post-surgical intra-
abdominal abscesses, is a particularly difficult therapeutic
area. The pathologically changed structures of cavital walls
and substantial amounts of pus inside cavities prevent
efficient administration of antibiotics. Also, many pathogens
causing endo-cavital infections have become antibiotic-
resistant.
The procedures used at present to deal with endo-
cavital infections are not as effective as is desired; a two
step therapy is generally used. First, the cavity is drained
to remove as much material as possible; this will include both
cell debris due to the infection and to some extent the
microorganisms causing the infection. Second, an antibiotic
medication is administered to the patient. If the
antibiotics) are to be successful, maximal cavity drainage is
essential. In order to achieve maximal drainage, a hollow
catheter is inserted cutaneously into the cavity either blindly
or with guidance. Guidance is normally effected either by the
use of an ultrasonic probe, or by the use of an endoscopic
fiber-optic device included in the drainage catheter. But
drainage is hampered by the flow characteristics of the fluid
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and pus containing cell debris being removed from the cavity,
and by the relatively small size of the catheter in comparison
with the potential volume of the cavity requiring drainage. An
additional problem is the unavoidable presence of
microorganisms both elsewhere in the cavity and on and around
the catheter. As a consequence of these difficulties, in
practice it is rarely possible to drain a cavity to the
desirable level. It is also of importance that there is a real
risk that some of the microorganisms are the so-called "super
bugs", which are mutant strains of common microorganisms such
as staphylococcus resistant to the currently available
antibiotics.
Endo-cavital infection-caused diseases, such as
destructive forms of tuberculosis and post-surgical intra-
abdominal abscesses, present a rapidly growing concern
internationally. In North America, post-surgical intra-
abdominal abscesses are a major post-operative problem for a
wide range of invasive surgical procedures. It has been
estimated that the percentage of patients, who develop post-
surgical intra-abdominal abscesses, ranges from about 30o for
colorectal surgery, through about 15o for pancreatic or biliary
surgery to about 2% for gynecologic surgery. Patients
undergoing intra-abdominal surgery in North America alone, on
an annual basis, number in the millions. These infections can
be traced to several causes, including both airborne
microorganisms and spontaneous leaks or perforations of either
the biliary tract or the intestines. In other words, any
procedure devised to treat such infections has to accommodate
the fact that the infection will almost certainly involve
several strains of microorganisms; each strain will respond
differently to any applied procedure.
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It has been reported by Apollonov et al. in RU
2141859 (issued in 1998) that laser-generated ultraviolet light
can be used in treating tuberculosis. By using a suitable
fiber-optic catheter, the laser-generated UV light is used to
irradiate and to destroy, within the lung cavern, the
microorganisms, which are the cause of the tubercular
infection. The method includes puncturing or draining the
destructive cavern in the lungs, evacuating the purulent
contents of the cavern and then exposing the interior surface
of the cavern to ultraviolet laser radiation. This involves 10
to 12 minutes of exposure to the defocussed pulsed radiation of
a solid-state laser at a wavelength from about 220nm to about
290nm, and energy density of 200 mWsec/cm' with the pulse
repetition frequency controlled as a function of the degree of
destruction in the lungs, to ensure irradiation with an average
energy density of 10 to 15 mWsec/cm~. A treatment session is
concluded with a single introduction of 1.0 units of
streptomycin or canamycin into the cavern. A course of
treatment comprises 10 - 12 sessions of laser irradiation of
the cavern.
However, there are several difficulties with the
apparatus and the procedure described by Apollonov et al.
These are as follows.
(1) The need for repeated puncturing of the cavern, which
increases the degree of trauma experienced by the patient.
(2) Before the procedure is carried out, each repeated
puncturing requires repeated radiological investigations, which
increase the X-ray dose to which the patient is subjected.
(3) Each treatment session is concluded with a single
introduction into the cavern of a full daily dose of an anti-
tubercular medication dissolved in 2 to 3 ml of a 0.5~ Sol.
Novocain. The introduction of a full daily dose of anti-
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tubercular medication in a single dosage unit does not permit
maintaining its bactericidal concentration within the cavern at
a steady level throughout a period of 24 hours. In addition,
because of the quantity involved, an introduction of such an
amount of anti-tubercular medication at once frequently causes
irritation of the mucous tissue of the bronchi draining the
cavern, and this leads to a debilitating cough and
expectoration in the sputum of a considerable quantity of the
anti-tubercular medication that was introduced into the cavern;
it also reduces the concentration of medication and lowers its
bactericidal effect.
(4) To irradiate the cavern, Appolonov et al. used the emission
of an available laser generating within the UV-C spectral range
(266nm, the fourth harmonic of the Nd:YAG laser). While that
wavelength is still capable of producing bactericidal effect on
tuberculosis pathogens, it is apparently not optimal for
destroying the majority of tuberculosis microorganisms. This
relationship is shown graphically in Figure 1. Inspection of
Figure 1 shows that the most efficient wavelength to kill
tuberculosis bacteria is about 250nm, and that some UV
wavelengths may not be efficient at all to treat tuberculosis.
At the same time, other bacteria are more susceptible to the
wavelengths efficient in the tuberculosis treatments. The use
of a UV light wavelength which is not the most efficient
wavelength, which is has specific value characteristic of each
microorganism strain, or class of strains, means increased
exposures, higher irradiation energy density and an increased
risk of side effects.
Usually, patients to receive antibacterial treatment
are already under a major stress, often with depressed immune
systems after having undergone a major invasive surgical
procedure, or suffering from a severe infection such as
CA 02395584 2002-08-09
S
tuberculosis or intra-abdominal abscess. Thus, it is very
desirable that any treatment procedure to deal with such
infections would expose the patient to as little further stress
as possible. It is therefore a prime concern to avoid having
to surgically re-enter the cavity. The traumatic levels
associated with repeated cavity re-entry implies that the level
of antibiotics required to control the so-called "super bugs"
may be more than the weakened patient can tolerate.
This invention results from establishing the fact
that the lethal dose required for a given microorganism depends
on the wavelength of the irradiating ultraviolet light. By
matching the wavelength of the UV light to a specific
microorganism, or class of microorganisms, the lethal dose is
optimized, the irradiation efficiency is increased and the risk
of damaging surrounding tissues is minimized.
It was shown in the Table 1 above that the lethal
doses of the W light are not the same for different strains of
microorganisms. The W-irradiation used in the measurements
summarized in Table 1 was spectrally non-selective. The
results of treating (in vitro) different microorganisms with
narrow band laser generated W light, spectrally matching the
most efficient bactericidal response (found by measuring curves
for various bacteria similar to that of F'ig. 1), are shown in
Tables 2 and 3. The average lethal doses for different
bacterial strains irradiated with narrow band laser light are
substantially lower as compared to those shown in Table 1.
TABLE 2. Measured average lethal doses for different
microorganisms (in mWsec) measured under specific
laser-line irradiation
s
CA 02395584 2002-08-09
LETHAL
Cavern DOSE
(mWsec)
Area Mico- St.AureusKlebsiella Entero- PseudomonasE.coli
(cmz) bacterium pneumonia bacter aeruginos
tubercul- aerogenes
osis
$ 28.3 45 85 141 198 141 141
50.3 80 151 251 352 251 251
78.5 126 236 393 550 393 393
113.1 181 339 565 792 565 565
153.9 246 462 770 1078 770 770
201.1 322 603 1005 1407 1005 1005
254.5 407 763 1272 1781 1272 1272
314.2 503 942 1571 2199 1571 1571
380.1 608 1140 1901 2661 1901 1901
452.4 724 1357 2262 3167 2262 2262
1$ 530.9 849 1593 2655 3717 2655 2655
615.8 985 1847 3079 4310 3079 3079
706.9 1131 2121 3534 4948 3534 3534
TABLE 3. Average lethal dose densities (dose/cm2) for
different microorganisms measured under laser-line
irradiation specific to each bacteria (based on the
Table 2 data).
AVERAGE
LETHAL
DOSE DENSITY
(mVJsec/cm=)
Micro-organism
Mico- St.AureuKlebsiellaEntero- PseudomonaE.coli
bacterium s pneumonia bacter s
tuberculosi aerogenesaeruginos
s
Dose/ 1.6 3 5 7 5 5
cm2
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Thus in a first broad embodiment this invention seeks
to provide a method for treating endo-cavital infections
comprising:
(a) determining the spectrum of microorganisms
present in the population of microorganisms in the
cavity causing the infection;
(b) determining a ranking of the relative amounts of
at least the major infecting microorganisms within
the population present in the cavity;
(c) selecting an ultraviolet light wavelength at
which the lethal dose in microwatt seconds/cm2is
minimised for at least the highest ranking
microorganism identified in step (b);
(d) draining the infected cavity to remove debris
contained therein;
(e) irradiating the interior of the cavity with
pulsed laser-generated ultraviolet light having a
wavelength close to the wavelength selected in step
( c ) ; and
(f) if required, repeating steps (d) and (e) until a
desired level of microorganism destruction has been
achieved.
In a second broad embodiment this invention seeks to
provide an apparatus for treating an endo-cavital microorganism
infection comprising in combination:
(A) a catheter device constructed and arranged to be
both insertable into and withdrawable from the
cavity;
(B) a laser generating device constructed and
arranged to provide at least one output of pulsed
ultraviolet light of known intensity and wavelength
of from about 200nm to about 700nm; and
CA 02395584 2002-08-09
(C) a drainage system constructed and arranged to
remove fluid debris from the cavity;
wherein:
(i) the catheter device includes at least one fibre
optic guide constructed and arranged to deliver
ultraviolet light generated by the laser device to a
locus within the cavity; and
(ii) the laser generating device is chosen from the
group consisting of a laser generating device
constructed and arranged to provide a beam of
ultraviolet light of a single predetermined
wavelength and intensity, and a laser device
constructed and arranged to provide a plurality of
beams of ultraviolet light each having a known
wavelength and intensity.
Preferably the at least one fibre optic device
constructed and arranged to provide a beam of ultraviolet light
is a single use device.
Preferably, the laser generating device is a tunable
Raman solid state laser. Conveniently, the laser generating
device is a diode pumped tunable Raman solid state laser.
Preferably, the catheter device includes at least a
fibre optic guide connectable to the laser and constructed and
arranged to permit illumination of the cavity, and a separate
pumpable drainage system.
Preferably, the catheter device additionally includes
a second fibre optic system constructed to permit viewing of
the interior of the cavity.
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Alternatively, the catheter device also includes an
ultrasonic probe system.
This invention derives from the discovery that,
although it is known that broad spectrum ultraviolet light is
lethal to a wide variety of known microorganisms, including
viruses which are extremely resistant to antibiotics, hitherto
it had not been fully understood that there is a "best"
frequency for each microorganism at which ultraviolet light is
most lethal to that microorganism. This permits the use of the
lowest dose, in microwatts/cm', to kill a given microorganism.
But this also raises a difficulty, which is that laser
generating devices provide a laser beam with only a very narrow
wavelength range: a laser provides an essentially monochromatic
beam. It then follows that if a laser device is used, although
such a device may be tunable to some extent to provide a
wavelength either at, or at least close to, the desired most
lethal wavelength, it will only provide one wavelength which
will be most lethal for only one microorganism (or a group of
closely similar microorganisms). But as noted above, in the
typical case of major invasive abdominal surgery the infections
are caused by more than one microorganism, typically a spectrum
of microorganisms is present in the population of
microorganisms in the cavity and the population as a whole is
causing the infection. To deal with such a broad spectrum of
microorganisms a plurality of laser devices will be required.
An alternative laser source has recently become
available which overcomes these difficulties. This is the so-
called diode pumped-solid state Raman laser. These are compact
solid state devices which operate at a high repetition rate and
can be configured to provide more than one output frequency by
interposing in sequence different Raman materials into the
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pulsed laser beam. These devices also operate reliably at high
pulse repetition rates of the order of 0.2kHz. It is thus now
possible to obtain what is effectively a tunable laser device
which can be tuned to be most lethal to more than one of the
microorganisms causing an infection in a bodily cavity either
after major invasive surgery, or due to other causes, for
example an inner ear infection. Laser devices of this type are
available from Passat Ltd, Toronto, Ontario, Canada. A typical
device can provide up to nine different wavelengths adjusted to
the needed wavelength within the range of from about 200nm to
about 1200nm. These devices are small, compact, require no
dangerous gases, and are well adapted to use in a medical
facility
The method provided by this invention requires as a
first step an assessment of the microorganisms in a given
population to identify both the members of the population and
to rank them as a proportion of the population. It is then
possible to assess the most lethal wavelength for each of the
microorganisms, for example by means of tests carried out on
microorganism samples from one of the available collections. A
data bank can then be developed which will cross reference each
microorganism to the most desirable irradiation frequency. As
but one example, it has been determined the most lethal
wavelengths for tuberculosis are at about 248nm and about
337nm, with the longer wavelength being far less effective. At
the same time as establishing the most lethal wavelength it is
also desirable to establish the most effective laser pulse
frequency.
The next step then is to provide a laser generating
device which will provide either the most desirable wavelength
for the highest ranking microorganism in the population, or for
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the three or four highest ranking ones. The interior of the
infected space is then irradiated to provide a desired
radiation dose in microwatts/cm2 to the infected locality
within the space. The patient is then monitored over suitable
time period to assess whether the cavity needs to be irradiated
a second time.
The irradiation at a selected wavelength or
wavelengths can also be accompanied by conventional antibiotic
therapy.
It is also contemplated that within the scope of this
invention that in order to minimise patent stress a single
multichannel catheter is used which will contain at least both
the fibre optics required for the laser and the channels
required for effective drainage and lavage. For the adequate
treatment of at least some endo-cavity infections it is
desirable for the medical personnel to be able to view the
inside of the cavity either directly using visible light fibre
optic devices or indirectly using an ultrasonic probe.
Catheter devices of this type are known; typical catheters of
these types including a laser capability, drainage channels,
and the like are described by among others by Johnson et al. in
US 5,437,660; Costello et al. in US 5,593,404 and Doiron et al.
in US 5, 957, 404 .
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