Safety and Feasibility Study of Methylene Blue Photodynamic Therapy to Sterilize Deep Tissue Abscess Cavities

Deep tissue abscesses remain a significant cause of morbidity, mortality, and hospital stay
despite improved surgical techniques and increasing use of perioperative antibiotics.
Mortality ranges from 80-100% in undrained collections and, in patients with intraperitoneal
abscesses, reported hospital stays have been 21-47 days. The development of image-guided
percutaneous drainage accompanied by antimicrobial treatment has been shown to improve
patient outcomes and can significantly reduce mortality in uncomplicated fluid collections to
5% and morbidity to 10-15%. Even under favorable conditions, the use of long-term antibiotics
increases the risk of acquired resistance and incidence of polymicrobial infection, which may
limit future options for antibiotic treatment. Further, in 23% of patients, percutaneous
drainage and intravenous antibiotics fail, requiring open surgical drainage, particularly in
patients with abscesses infected with yeast or abscesses due to a pancreatic process.

Photodynamic therapy (PDT), which exerts antimicrobial activity through the generation of
reactive oxygen species, may serve as a useful adjunct to current standard care of treating
deep tissue abscesses by reducing the microbial burden following drainage. Recent work from
our group demonstrated the effectiveness of methylene blue photodynamic therapy (MB-PDT)
against organisms within primary aspirate fluid obtained from 32 patients who underwent
image-guided percutaneous drainage of an abscess cavity. We found that MB-PDT was effective
against multiple classes of organisms, including yeast and those displaying drug resistance.
In these complex samples, we found no evidence of resistance to MB-PDT. These preclinical
results obtained with samples harvested from the kinds of abscesses that we propose to treat
provide a compelling rationale for evaluating the technical feasibility and safety of
advancing optical fibers through catheters into an abscess cavity and performing PDT at the
time of drainage. This clinical strategy would offer a wide range of potential health
benefits to patients with deep tissue abscess. Among these advantages are reduced surgical
intervention, decreased spread of infection, shortened course of post-treatment antibiotic
therapy, and decreased selective pressure for antibiotic resistance. Ultimately, this would
promote early recovery, shorten hospital stay, and lead to lower overall health care costs
for patients undergoing image-guided percutaneous abscess drainage.

Image guided percutaneous drainage is performed at the University of Rochester using CT,
ultrasound, or fluoroscopy. Focused imaging is performed, which confirms that the collection
is amenable to drainage. The site is prepared and draped in the usual sterile fashion. The
overlying skin is anesthetized with 1% lidocaine. A Hawkins/micropuncture needle is inserted,
and the location confirmed under image guidance. The needle is advanced and placement within
the collection is confirmed with imaging. Syringe aspiration of the abscess material is
collected and sent for gram stain and culture. The needle is exchanged for a dilator and the
018 wire is replaced with a Coon's wire. If abscess collection contains multiple loculations,
the end of the Coon's wire will be used to break up the loculations. The tract is further
dilated with a transitional dilator followed by placement of an appropriate sized All Purpose
Draining Locking pigtail catheter (8-14 French) into the fluid collection. The abscess will
be drained by aspiration with a syringe. The catheter will be secured to the skin using 2-0
silk or stat-lock, dressed appropriately and connected to a drainage bag.

After drainage, the cavity will be flushed with sterile saline as per routine procedure.
Following this, and using the same catheter, the cavity will then be filled with sterile,
clinical grade methylene blue solution diluted 10-fold from its stock concentration of 10
mg/mL. The volume introduced will be matched to the cavity volume, which we estimate will not
exceed 270 mL. This dose is within the therapeutic range used for methylene blue. In the
unlikely case of the entire methylene blue dose escaping into systemic circulation, this
results in a full body dose of 3.85 mg/kg for a typical patient weight of 70 kg. This is
below the range for which adverse events have been reported for methylene blue.

After a 10-minute incubation interval, the methylene blue solution will be aspirated from the
cavity and flushed twice with sterile saline. The cavity will then be filled with sterile 1%
Intralipid solution to gently distend the cavity and, through efficient light scattering, to
homogenize the light dose to the walls of the cavity.

A sterile, FDA-approved optical fiber will be advanced to the approximate center of the
abscess cavity via the same catheter under image guidance. The proximal end of the fiber is
coupled to the output of a diode laser system emitting light at 665 nm, where methylene blue
is activated optimally. Laser power will be delivered to the cavity at a constant fluence
rate at the wall of 10 - 20 milliWatts (mW) cm-2. The laser power required to obtain the
desired fluence rate at the wall will be calculated and documented on a written form in the
procedure room based on the abscess size, with total laser power in the range of 1-2 W. The
diode laser system being used is capable of measuring optical power, and will be used to
directly measure the output from the optical fiber before treating each patient. These
fluence rates are within an appropriate range for effective photodynamic therapy but well
below the intensity at which modest thermal effects are observed in tissue. Immediately after
laser irradiation, the Intralipid solution will be aspirated and the cavity again flushed
with sterile saline.

Fluence escalation will be accomplished by systematically incrementing the duration of laser
exposure according to a "3 + 3" dose escalation scheme. Under this design, the first three
patients will receive a 5 minute exposure of laser light. If no dose-limiting toxicities are
encountered, the exposure duration will be increased by 5 minutes in the next group of three
patients. If one dose-limiting toxicity is encountered, the next group of patients will
receive the same exposure duration as the previous group. If two or more dose-limiting
toxicities are encountered, the exposure will be de-escalated by 5 minutes. This process will
continue until the maximum number of patients are treated, or 6 patients are treated at a
de-escalated dose. In order to avoid excessive increases in procedure duration, the maximum
duration of laser exposure will be 30 minutes. A dose-limiting toxicity is defined as
diminished clinical condition, with evidence of one or more of the following: (i) evidence of
fat embolism; (ii) methylene blue escape during procedure with evidence of adverse reaction;
(iii) imaging evidence of clinically significant, therapy-induced disruption of the abscess
wall and damage to surrounding tissue.

Antibiotics as prescribed by the subject's primary team will be administered before the
procedure and continued post-procedure. These are selected to ensure adequate coverage and
taking into account subject allergies. Such administration is considered the standard of
care, and serves to reduce the rate of post-procedure sepsis. The subject will also be
administered intravenous antiemetics as needed prior to the procedure for nausea.

Following the procedure and as per routine care, a combination of IV and PO antibiotics will
be continued to reduce the rate of post procedure sepsis. Antiemetics will also be continued
as needed to reduce symptoms of nausea and vomiting. Narcotics will be prescribed and
administered to control pain symptoms.

If the subject is an inpatient at the time of drainage, he/she will remain hospitalized
post-procedure. If the subject is an outpatient at the time of drainage, he/she will be
admitted to the hospital post-procedure only if clinically warranted. The study doctor or his
designate will visit hospitalized subjects daily to assess progress and AEs. The subject's
clinical course will be discussed daily with the primary clinical team. Hospitalized subjects
will be discharged based upon response to drainage and clinical course only if clinical
indicators (white blood cell count, heart rate, blood pressure, and temperature) are stable.
If the subject remains hospitalized as a result of underlying health issues that are
unrelated to study participation, the study doctor or his designate will continue daily
visits through day 5 post-procedure, hospital discharge or until the drain is removed,
whichever comes first. The PI will follow up with all non-hospitalized subjects daily by
telephone through 7 days post-procedure.

All subjects will be seen again at one week following the procedure to further assess for
progress, AEs and abscess resolution. As per departmental protocols and procedures, if the
abscess has resolved at day 7 as evidenced by catheter output of less than 20 cc daily and
limited imaging of the abscess cavity, the drainage catheter will be removed. If the abscess
persists beyond 7 days despite drainage, the catheter will remain in place and be evaluated
again at day 14. If the abscess persists at day 7 and if clinically indicated, additional
procedures (i.e. repeat draining with a larger diameter catheter) will be performed. MB-PDT
will not be repeated. Abscess resolution will be determined by either ultrasound or CT scan
as outlined below. Imaging at the time of catheter removal is considered standard of care.

A study visit at day 7 post procedure is required of all subjects. If the catheter is left in
at that time, a second visit will be required at day 14. If the catheter is removed at day 7
and there are no unresolved AEs, subject study participation will end after that visit. If
any subject cannot return as has been scheduled, the visit will be rescheduled to their
convenience. The visits at 7 and, if necessary, 14 days post procedure are primarily to
determine the timing for catheter removal and are standard of care following percutaneous
drainage.

At a minimum, CBC w/ diff and serum creatinine will be acquired prior to the procedure. Blood
cultures will be obtained as clinically indicated, and drainage cultures will be obtained at
day 0. Additional laboratory and imaging studies will be performed as deemed clinically
necessary.

There is very minimal risk of systemic skin photosensitivity after exposure to methylene
blue. Based on studies of the pharmacokinetics of methylene blue, it was found that the
majority was rapidly converted to leucomethylene blue, which is photodynamically inactive. In
clinical studies of MB-PDT with MB administered intratumorally, intravesically, and via
gargling, no skin photosensitivity was reported. Subjects will be monitored for any evidence
of skin photosensitivity reaction after the procedure. Due to the rapid conversion of MB to
leucomethylene blue in systemic circulation and the lack of photosensitivity in previous
studies, no special precautions will be taken to limit the exposure of subjects to light
after the procedure.

The 21 subjects enrolled in the study will be followed until all clinical findings post
image-guided drainage and MB-PDT have cleared. Each subject will be evaluated by imaging and
laboratory studies at scheduled visits 7 days post procedure and, if necessary, 14 days post
procedure. It is estimated that this study will take approximately 1 year to complete.

Inclusion Criteria:

- Adults 18 years or older

- If female, patient must have negative pregnancy test

- All patients with clinical symptoms (ex: fever, chills, pain, tachycardia,
hypotension), laboratory (leukocytosis) and radiologic findings (thick walled,
rim-enhancing collection with gas bubbles or air-fluid levels) compatible with an
abscess that requires image-guided percutaneous drainage

- Abscess cavity diameters will be less than or equal to 8 cm. However, abscess can be
complex or loculated

- Approval by the primary care team to pursue PDT and discuss enrollment with the
patient

Exclusion Criteria:

- Pregnancy

- Lactation

- Allergy to contrast media, narcotics, sedatives, atropine or eggs

- Necrotic tissue that requires surgical debridement

- Severely compromised cardiopulmonary function or hemodynamic instability

- Thrombocytopenia (<50,000/mm3)

- Uncorrectable coagulopathy

- Poor kidney function (serum creatinine >3mg/dl)

- Lack of a safe pathway to the abscess or fluid collection

- Unable or unwilling to understand or to provide informed consent

- Unable or unwilling to undergo study procedures

- Patient unable to cooperate with, or to be positioned for the procedure

- Unable to comply with necessary follow up

- Abscesses greater than 8 cm in diameter, multiple separate abscesses in different
locations, and abscesses not amenable to safe percutaneous image-guided drainage.

- Patient is currently taking serotonergic psychiatric medication