Q&A with Paul Ducheyne of XeroThera, Inc.

XeroThera has developed an antibiotics delivery vehicle (a biocompatible, resorbable microparticle) that can be used prophylactically. It can be mixed in minutes, at the time of surgery, with any antibiotic of choice (on the part of the surgeon); still, the medicine is only released in a very controlled fashion over days up to two weeks. Antibiotics typically used in orthopaedic surgery such as gentamicin, vancomycin, rifampin, etc… can be administered and released. Thus, XeroSyn, XeroThera’s first product is designed to reliably and continuously deliver potent antibiotic (or antibiotics) selected directly to the surgical wound at implantation, and to slowly release further antibiotics throughout the initial postoperative convalescence period.

There are many advantages to the XeroSyn product concept. The product is not a medicine, but a very biocompatible material. Thus, the path to market is much shorter than for new treatment concepts with drugs enclosed. This implies that development duration of the product is much shorter (about 3 years instead of about 6 years), and that accordingly, also development costs will only be about 20% of the development cost of a delivery material with ready included antibiotics. In the US, a 510(k) pathway to market can be pursued. In their pre-surgical planning, surgeons can select the antibiotic (or antibiotics) most appropriate for the case at hand. Typically, one will select an antibiotic against gram positive bacteria, such as gentamycin or vancomycin, but also drugs effective against gram-negative bugs, can be selected, if warranted. Furthermore, if there is concern regarding resistant strains, two antibiotics such as vancomycin and rifampin can be added, and still there is a controlled release of both to the wound site. Obviously, local, controlled delivery from XeroSyn has all the benefits of local delivery as opposed to systemic delivery (intravenous injection). In fact, there is a local high concentration of the released molecules, and a much lower concentration in the blood stream, just the opposite as for intravenous administration.

The treatment of bone infection mainly involves operative debridement, removal of all foreign bodies and antibiotic therapy. Usually, intravenous antibiotics are prescribed for 3 weeks, followed by 3 weeks of oral antibiotics. In order to achieve an effective local drug concentration, a high parenteral dose of antibiotic must be administered. In addition, a prolonged course of treatment is needed. Both can lead to systemic toxicity of the antibiotic. Regardless, there are still significant relapse rate, even with such vigorous treatment programs. There has been increasing interest in products providing local antibiotic therapy. In principle there are advantages to local antibiotic delivery, because putatively a high antibiotic concentration can be achieved where it is needed, namely locally. However, today’s reality does not lead to such sanguine assessment. Non-biodegradable delivery systems such as poly(methylmethacrylate) (PMMA) beads containing gentamicin are routinely used in the treatment of osteomyelitis. However, the pharmacokinetic profile of antibiotic released from PMMA beads is far from ideal. In vitro pharmacokinetic and in vivo animal studies demonstrated a peak local antibiotic concentration on the first day followed by a drop-off by several orders of magnitude which is known as “initial burst” release. As such a therapeutic concentration is not maintained for the desired two to three weeks. A second major drawback is the need for a second surgery to remove the delivery system. When left in situ for too long, the beads are actually difficult to remove. A third drawback is that the continuous low dose delivery past the first day, typically at a concentration significantly below the minimal inhibitory concentration (MIC), and the extended period of slow delivery, create conditions potentially facilitating bacterial resistance development. Other approved products in European markets (not approved in USA) are a Gentamicin-impregnated collagen sponge and tobramycin impregnated calcium sulfate bone grafts. These materials also suffer from very high initial burst release and are unable to deliver antibiotics for more than 48 hrs, due to the fast degradation of the carrier. The standard of care for prophylaxis is pre-operative vancomycin IV injection, but this leads to the incidence of infections stated above.