Ultrasonic Drug Dispersion (UDD)
Subcutaneous delivery of antibiotics followed by external ultrasonic dispersion has been adapted from plastic surgery procedures used during liposuction and body contouring and is proposed as a new approach to an old problem. The antibiotic used in our current research is cefazolin (Ancef, Kefzol) mixed in a specific volume of saline which is introduced into the surgical area just prior to the incision being made, and after the patient has been anesthetized. The fluid is dispersed deeply into the subcutaneous tissue layer by application of external ultrasound. Any subsequent procedures then proceed in the usual fashion. Theoretical constructs underpinning the intervention are delivery of antibiotics directly to the wound site at the time of greatest need and prevention of tissue dehydration during exposure to air to decrease potential tissue necrosis. Dispersing the antibiotic directly into the tissue just prior to incision ensures high local tissue levels at the time when antibiotic protection is most needed.
Phase 2 Expanded Access Clinical Study
In December of 2013, we commenced an FDA-approved expanded access clinical study for Ultrasonic Drug Delivery for serious skin and skin structure infections (SSSIs). This study was performed at Palm Drive Hospital (later renamed to Sonoma West Medical Center) in Sebastopol, California, under the supervision of the Western Institutional Review Board (WIRB). Twenty patients completed the study. All patients had failed standard IV and oral antibiotic therapy prior to being enrolled in this study. All data was collected and recorded by designated members of the hospital medical staff and submitted to the FDA. The results of this study were very promising and we are moving forward with a comparative Phase 2 trial.
Phase 2 Comparative Clinical Study
We are currently developing a comparative randomized study where we will compare IV drug delivery to Ultrasonic Drug Dispersion (UDD). Prior to this study, other than topical applications, antibiotics have always been given systemically either orally, intramuscularly (IM) or intravenously (IV). Sometimes an antibiotic must be given systemically because that is the only method to access the infection, for example, with pneumonia, meningitis, or a kidney infection. However, if the infection is located in soft tissue that is readily accessible, then direct delivery of antibiotics becomes an option worth exploring. Since this method does not depend on blood supply to reach the target area, it may be especially advantageous to those with impaired circulation such as diabetic patients.
Our study is registered at ClinicalTrials.gov (NCT01238276).
Phase 1 Pilot Study
In May of 2007, a Phase I pilot study was commenced at Santa Rosa Memorial Hospital, Santa Rosa, California under their IRB. The objective of this phase of the study was to assess tissue levels of cefazolin following traditional intravenous administration with subcutaneous administration using a tissue dispersion technique in a small sample of patients undergoing elective abdominoplasty. The concentration was so much higher in the ultrasound group than the intravenous group that the study continued only using ultrasonic dispersion. David P. Nicolau, PharmD FCCP, FIDSA, Director of The Center for Anti-Infective Research and Development at The Hartford Hospital, measured tissue and serum levels of cefazolin using a validated HPLC method and the differences were quite significant. There were no adverse reactions. All patients were done as outpatients, healed with minimal pain, and had uneventful recoveries.
Based on the results from this pilot study, Dr. Nicolau titrated cefazolin against several highly resistant strains of Methicillin-resistant Staphylococcus aureus (MRSA). The result was a minimal inhibitory concentration (MIC) average of 188 micrograms/ml with the median of 169 micrograms/ml., the most resistant being 512 micrograms/ml. The concentrations achieved in that study were sufficient to destroy the most resistant forms of MRSA, a Gram-positive bacteria, with cefazolin. The foregoing results suggested the possibility of successful treatment of MRSA infections using cefazolin delivered in this manner and in this concentration.
Dr. Nicolau and Dr. Silberg have published the results of a study in Infectious Drug Resistance* where 1,239 MRSA isolates were tested against cefazolin, which demonstrated that cefazolin is effective against even the most resistant strains of MRSA if a high enough concentration can be achieved at the target site. See Publications for more information.
In addition to the patients treated in our clinical study, 108 patients were treated off-label (29 under an IRB) with cefazolin or ceftazidime using UDD, with informed consent, at Santa Rosa Memorial Hospital (Santa Rosa, California), and The Advanced Surgery Institute (Santa Rosa, California). The results have been very promising.