Efficacy of Methylene Blue Photodynamic Therapy for Treatment of Deep Tissue Abscesses

A Phase 2 Study to Assess Efficacy of Methylene Blue Photodynamic Therapy for Treatment of Deep Tissue Abscesses

The objective of this Phase 2 study is to evaluate the efficacy of methylene blue photodynamic therapy (MB-PDT) performed at the time of percutaneous abscess drainage for disinfection of deep tissue abscesses. The study includes three arms: (1) MB-PDT at a fixed drug/light dose plus standard of care abscess drainage , (2) MB-PDT at a patient-specific dose determined by pre-treatment optical measurements plus standard of care abscess drainage , and (3) standard of care abscess drainage. The primary endpoint is reduction in bacterial burden from pre- to post-intervention, quantified by culture of abscess aspirates.

Abscesses form as a result of the interaction between an acute microbial infection and the host immune system, and generally result in fever, nausea, and acute abdominal pain. If untreated, the mortality rate can be high. Abscesses are routinely managed by image-guided percutaneous drainage and delivery of systemic antibiotics. Despite this standard of care, abscesses remain a significant source of morbidity, mortality, and hospital stay. Further, response can vary widely between patients. Many abscesses also contain antibiotic resistant species. Photodynamic therapy (PDT), which relies upon the combination of photosensitive dyes known as photosensitizers, excitation by visible light, and molecular oxygen to generate cytotoxic reactive oxygen species, represents a powerful adjunct to standard of care drainage. A Phase 1 clinical trial aimed at assessing the safety and feasibility of methylene blue (MB) PDT at the time of percutaneous abscess drainage (ClinicalTrials.gov Identifier: NCT02240498) was completed. No adverse or serious adverse events were observed, and the procedure was well tolerated by all subjects. However, this Phase 1 study was not designed or adequately powered to evaluate efficacy of MB-PDT, and did not include objective assessment of treatment efficacy. The current study therefore aims to assess efficacy of MB-PDT by analysis of pre- and post-PDT samples. This is a single center, randomized, open-label Phase 2 clinical trial, which will be conducted in accordance with the principles of good clinical practice and following approval by both the FDA and local IRB. Patients who have been diagnosed with a drainable abscess, that meet all inclusion/exclusion criteria, and have the approval of their primary care team, will be offered enrollment in the study. Consented subjects will be assigned prospectively to one of three arms: (1) MB-PDT at a fixed drug/light dose plus standard of care abscess drainage, (2) MB-PDT at a patient-specific dose determined by pre-treatment optical measurements plus standard of care abscess drainage, and (3) standard of care abscess drainage alone. The primary endpoint is reduction in bacterial burden from pre- to post-intervention. Secondary endpoints include change in white blood cell count and blood cultures from pre-intervention to 24 hours post-intervention, drain output following intervention, and resolution of clinical symptoms. All subjects will receive standard of care image-guided percutaneous abscess drainage. This includes collection of a pre-intervention abscess aspirate sample, and placement of a drainage catheter. For subjects in Arms 1 and 2, sterile methylene blue (MB) will then be administered to the abscess cavity using the same needle/catheter utilized for standard of care drainage. After a 10 minute incubation interval, MB will be aspirated and the cavity flushed with sterile saline. For subjects in Arm 2, optical spectroscopy measurements will then be made to determine the optical properties of the abscess wall. This will be done by connecting the proximal end of the sterile optical fiber used for treatment illumination to a custom optical spectroscopy system. The distal end of this fiber will be advanced through the same catheter/needle used for the standard of care procedure in order to make gentle contact with the wall of the cavity. Low-intensity white light will be delivered by the fiber, and light that has interacted with the abscess wall will be detected by the same optical fiber. These optical measurements will be averaged and used to extract the absorption and reduced scattering coefficients at the treatment wavelength. These extracted optical properties, along with the subject's segmented pre-procedure CT images, will be used to generate a patient-specific treatment plan that seeks to deliver a desired fluence rate to 95% of the abscess wall, while limiting the portion of the abscess wall that receives a high fluence rate (>400 mW/cm2) to less than 5%. For subjects in Groups 1 and 2, the cavity will then be filled with sterile 0.1% lipid emulsion solution to gently distend the cavity, and through efficient light scattering, homogenize the light dose to the walls of the cavity. A sterile optical fiber will be advanced to the approximate center of the abscess cavity via the same catheter/needle under image guidance. The proximal end of the fiber is coupled to the output of a diode laser system emitting light at 665 nm. For subjects in Group 1 (MB-PDT at a fixed dose), laser power will be delivered to the cavity at a constant fluence rate. The laser power required to obtain the desired fluence rate at the wall will be calculated purely based on the abscess size. For subjects in Group 2 (MB-PDT with patient-specific treatment planning), the subject's measured optical properties and their segmented pre-procedure CT images will be integrated with treatment planning software to determine the laser power required to deliver the desired fluence rate to 95% of the abscess wall, while limiting the portion of the abscess wall that receives a fluence rate of >400 mW/cm2 to less than 5%. In both cases, illumination will be delivered for 20 minutes, resulting in a total delivered fluence of 24 J/cm2. Immediately after laser irradiation, the Intralipid solution will be aspirated and the cavity again flushed with sterile saline. Collection of aspirated abscess material for microbiological assessment is standard of care for percutaneous abscess drainage. A portion of this standard of care collection will be collected by the study team for additional quantitative evaluation. Additionally, a post-intervention aspirate sample will be collected for study purposes. For subjects in Groups 1 and 2 (MB-PDT), this sample will consist of the aspirated saline used to flush the abscess cavity after Intralipid aspiration. For subjects in Group 3, this sample will consist of the aspirated saline used to flush the cavity following drainage. If successful, this research could result in an adjunct treatment for abscess patients that improves long-term abscess resolution and the rate of response to percutaneous 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.

The study includes three arms: (1) MB-PDT at a fixed drug/light dose plus standard of care abscess drainage, (2) MB-PDT at a patient-specific dose determined by pre-treatment optical measurements plus standard of care abscess drainage, and (3) standard of care abscess drainage.

The subject and study doctor will not be masked to group assignment, as it would be difficult or impossible to do so and unethical to subject patients to sham procedures if they are not assigned to a PDT group. However, all follow-up and subsequent data collection will be performed by a member of the study team that is masked to group assignment. Group assignment will only be unmasked to the study biostatistician at the time of statistical analysis. The remainder of the study team will only be unmasked after final results are published. This will reduce the potential for bias in collection of follow-up data, and protect the integrity of the study.

Each subject in this arm will receive standard of care abscess drainage, methylene blue, lipid emulsion, and laser illumination at an optical power defined by their abscess size.

Each subject in this arm will receive standard of care abscess drainage, methylene blue, lipid emulsion, optical spectroscopy, and laser illumination. The optical power for laser illumination will be determined by their abscess morphology and the results of optical spectroscopy.

Administration of 0.1 mg/mL methylene blue to the abscess cavity, followed by a 10 minute incubation interval. After this incubation interval, the methylene blue solution will be aspirated from the cavity and flushed twice with sterile saline.

The abscess cavity will be filled with sterile 0.1% lipid emulsion solution to gently distend the cavity and, through efficient light scattering, to homogenize the light dose to the walls of the cavity. After laser illumination, the Intralipid will be aspirated from the cavity.

A sterile, FDA-approved optical fiber will be advanced to the approximate center of the abscess cavity via the drainage catheter under image guidance. Following laser illumination, the fiber will be withdrawn.

Laser illumination will be delivered via the optical fiber for a duration of 20 minutes. The optical power will be set such that the fluence rate at the abscess wall due to ballistic photons is 20 mW/cm2.

The same sterile optical fiber used for treatment will be advanced through the drainage catheter/needle in order to make gentle contact with the wall of the cavity. Low-intensity, polarized white light will be delivered by a tungsten halogen lamp by the fiber, and captured by the same fiber. Light that has been de-polarized by interaction with tissue will be detected by a spectrometer and analyzed to extract tissue optical properties. Upon completion of these measurements, the fiber optic will be withdrawn, gently wiped with sterile gauze, and returned to the procedure cart.

Laser illumination will be delivered via the optical fiber for a duration of 20 minutes. The optical power will be set to deliver a fluence rate of 20 mW/cm2 in 95% of the abscess wall, based upon abscess morphology and optical spectroscopy results.

Following standard practice, a drainage catheter will be placed in the abscess cavity and used to aspirate purulent fluid.

The primary outcome is log10 reduction in colony-forming units per mL (CFU/mL) of bacteria in aspirate samples collected before and after intervention.

Daily output from the placed drainage catheter will be followed from the day of intervention to the either 14 days post-intervention or removal of the drainage catheter, whichever comes first. Daily drainage volume will be recorded, and cumulative drainage volume for the entire catheter placement will be reported.

Daily report of fever, chills, pain, heart rate, and blood pressure. The first day on which there is no report of fever, chill, or pain, and where heart rate and blood pressure are within normal ranges for the subject, will be recorded as the date of clinical symptom resolution. The mean number of days from intervention to symptom resolution will be recorded for each arm.

Inclusion Criteria: Adults 18 years or older 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 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 Abscess greater than 13 cm in diameter