How it All Began
In 2003, Barry N. Silberg, M.D., was asked to research why there were so many complications in legs when saphenous veins had been harvested using an open technique in patients undergoing Coronary Artery Bypass Graft (CABG) surgery. After observing several cases, he suspected tissue dehydration and contamination to be the cause. When opened during surgery, exposed subcutaneous adipose tissue immediately begins to dry out. Ambient bacteria lands on the dehydrated and damaged tissue, which ultimately gets closed within the wound leaving the body to destroy the bacteria and eliminate the necrotic tissue. A battle begins: If the body wins, there is no infection; if it loses, there is infection. In any case, the amount of pain is proportional to the inflammatory reaction. It has been determined that there is a direct correlation between the length of time a surgery takes and the degree of post-surgery complications or infections. Dr. Silberg’s research led him to develop a device for super-hydration of subcutaneous tissues prior to open saphenous vein harvesting in CABG surgery. He discovered that hydration of the tissue prior to surgery dramatically reduced the incidents of complications and post-operative pain. Dr. Silberg obtained FDA clearance for the Silberg Tissue Preparation System based on these data (Silberg TPS), which is manufactured by Mettler Surgical (Mettler ME800). This device is sold and marketed for ultrasonic dispersion of subcutaneously injected tumescent fluid. While the first use of the Mettler ME800 was for hydration of subcutaneous tissues prior to open saphenous vein harvesting, it has proven to be very effective for super-hydrating tissue before any surgery and for liposuction. Super-hydration of the tissue results in fewer complications, less pain, and faster healing. Next, Dr. Silberg reasoned that antibiotics could be delivered in the fluid that was being defused into the subcutaneous tissue.
Investigational New Drug
Dr. Silberg obtained an Investigational New Drug (IND) number, and, under an Institutional Review Board (IRB)-approved Phase 1 pilot study, he demonstrated the difference between locally infused Cefazolin dispersed with external ultrasound compared with the same dose being delivered intravenously. The study was done on healthy women undergoing elective abdominoplasty where some patients received Cefazolin through Direct Antibiotic Delivery (DAD) and some received Cefazolin through standard intravenous delivery methods. Tissue samples were sent for analysis to David P. Nicolau, PharmD FCCP, FIDSA, Director of The Center for Anti-Infective Research and Development at The Hartford Hospital. Although the sample pool was relatively small, the resultant difference in concentration was dramatic. It was determined that almost 400 x concentration could be achieved in the target tissue using this method when Cefazolin was delivered at a concentration of one gram/250ml saline.
During the course of this study, a 79 year old man, who had an MRSA infection on his chest, required an urgent sternotomy. Because a much higher concentrations of Cefazolin had been demonstrated when given directly using DAD, and because one gram of Cefazolin can be safely injected in 2.5 ml of saline intramuscularly, at the request of the cardiac surgeon and after obtaining informed consent, Cefazolin was infused at a concentration of 1 gram in 100 ml of saline under the pre-sternal skin and was dispersed with external ultrasound using the Mettler ME800. The wound healed painlessly and without incident. As an incidental finding, the MRSA infection in the treated area healed.
These results led to further tests in the microbiology lab where the most resistant strains of MRSA were tested against Cefazolin at various concentrations. These tests were conducted by Dr. David Nicolau, who titrated several strains of MRSA with controls against increasing concentrations of Cefazolin. The result was an effective MIC of Cefazolin against MRSA averaging188 µ/ml., with the median of 169 µ/ml., the most resistant being 512 µ/ml. These MIC levels were far in excess of any concentration attainable by any method other than DAD. We had proven the effectiveness of Cefazolin against the most resistant strains of MRSA was concentration dependent.
One gram of Cefazolin can be injected intramuscularly in as little as 2.5ml. With such low tissue toxicity, it seemed that injecting a gram of Cefazolin in 100ml, 1/40 of the accepted concentration would be safe. However, this had never been tested.
An opportunity arose when Dr. Silberg was asked to consult on a 73- year-old woman with type 2 diabetes who had been a smoker for over 40 years and had been hospitalized for 36 days. She had sustained a wound on her lower leg over the tibia in a bicycle accident and she now had an extremely painful open wound that was infected with MRSA that had not responded to multiple courses of intravenous antibiotics and debridement. After consent was obtained, she was treated with Cefazolin at one gram/100ml saline. A total of 10 ml was injected (0.1gm) followed by a small rotation flap and skin graft. Her pain was immediately relieved and her wound healed completely, with no recurrence.
Thus began an increasing call for treating patients who had failed standard therapy, some of whom were at risk of amputation. The success was almost complete without a single adverse event in 108 patients. Eighty-five percent required only one treatment. The most extreme case was a 450 pound man with diabetes who had Fournier’s gangrene (necrotizing infection of the groin) with a culture of MRSA. Dr. Silberg was consulted after the urologist had debrided all the necrotic tissue. The wound was treated with DAD using Cefazolin followed by closure over a drain. The patient healed completely and was discharged in eight days.
What we observed was the ability to deliver an antibiotic directly into infected tissue independent of blood supply. Cefazolin could be injected in higher concentrations than had ever been achieved before. Even a drug like vancomycin could possibly be injected directly at a concentration of 10µg/ml allowing an infection to be treated with as little as 0.1 mg thus avoiding the complications associated with large intravenous doses. This was especially important in patients with diabetes with severe infections of the lower extremity. A recent study demonstrated that 90% of amputations in diabetics are due to an uncontrollable infection.*
Based upon these anecdotal data, an FDA clinical study was initiated to demonstrate the safety and effectiveness of this technique and to further explore the mechanism of action of this new method of antibiotic delivery. We completed our first cohort of ten patients at Palm Drive Hospital, Sebastopol, CA.
*Lavery, L. A., Armstrong, D. G., Douglas, P. M., Peters, E. J. G., & Lipsky, B. A. (2007) Validation of the Infectious Diseases Society of America’s Diabetic Foot Infection Classification System. Clin Infect Dis. 44(4): 562-565.