Reports of serious disability and death resulting from contaminated allografts in patients who received donor tendons, ligaments, cartilage and bone grafts are growing. Just last month the FDA shut down a substantial part of the CryoLife Corporation, the nation's largest processor of donated human tissue, saying the company could not ensure that its soft-tissue products were free of deadly bacteria and fungi. In this article, experts outline five ways to minimize the risk of bacterial allograft contamination in your donor recipients.

1. Ensure tissue bank accreditation.
Experts say the best way someone who is not a tissue bank expert can ensure a basic level of quality is to use an American Association of Tissue Banks (AATB) accredited supplier. Regulatory oversight of tissue banks is lacking when it comes to bacterial contamination - making accreditation the most important safety net. Although the FDA requires tissue banks to follow certain quality control methods to prevent disease transmission, the agency's focus has been on infectious viruses such as HIV and hepatitis - and not on infectious bacteria.

In addition, tissue harvesters have no prerequisite qualifications even though they must collect tissue under sterile conditions, says Warren D. King, MD, orthopedic surgeon with the Palo Alto Medical Foundation. Dr. King also notes that there are no universal tissue processing standards, nor is there a centralized adverse event reporting system for allograft-related infections. (Dr. King and his colleague, Scott A. Barbour, MD, have reported on four cases of Clostridium septicum infection following ACL cases with contaminated allografts - all of which had significant clinical sequelae.) Further, only New York and Florida require state licensing and inspection of tissue banks.

AATB accreditation lasts for three years. While its focus is tissue procurement, AATB accreditation also covers safety, quality control and record keeping. Accreditation is largely voluntary, and just 74 of the estimated 160 full-service tissue banks are AATB-accredited. CryoLife is not AATB-accredited, and Dr. Eastlund feels it would have made a difference in this case.

Could Tissue Become Infected in the OR? Last November, a 23-year-old man died shortly after receiving knee tissue. Since then, the CDC has logged 52 reports of allograft-associated bacterial infections, most of which involve ACL replacements. Investi-gations revealed quality control issues in the tissue bank industry and prompted FDA to order a recall of allograft tissues at the CryoLife Corporation. Not all of the cases, however, are traceable to a tissue bank. In at least two cases, epidemiologic evidence rules out the tissue supplier as the source, suggesting that the grafts became contaminated in the OR, according to D. Ted Eastlund, MD, Blood Bank Director with the University of Minnesota's Lab Medicine/Pathology Department and past-president of the American Association of Tissue Banks (AATB).

2. Ask about FDAinspections.
The FDA requires tissue banks to register with the agency. FDA also attempts to inspect "full-service" tissue banks every two years, placing priority on unaccredited facilities and banks with a history of quality control problems. As of January 2001, FDA had inspected 118 full-service tissue banks and required or suggested quality improvements at 83 percent of them. Since then, the agency reports that it has inspected all of the estimated 160 full-service tissue banks but that an unknown number of other, ?partial-service' players still exist. These ?facilities' may harvest tissue but not process it, process tissue but not distribute it or only distribute tissue.

"Just because something is labeled as one tissue bank doesn't mean [it] did the processing," says Marion A. Kainer, MD, Epidemic Intelligence Service Officer with the CDC, at a recent meeting of FDA's Blood Products Advisory Committee. "Once consent is obtained from a donor, tissue is procured by sometimes several ? procurement organizations ? One tissue procurement organization may send tissue to several tissue processors. Thus, a single processor may then distribute it to several distributors, and then it gets implanted into multiple patients."

Dr. Eastlund recommends asking your supplier some hard questions about its history with FDA. For one, he says, ask your tissue bank if it has ever been inspected. If so, request a copy of the inspection report and ask if the FDA issued any warnings. If your requests are refused, you may want to change suppliers. Or, suggests Dr. Eastlund, use the Freedom of Information Act to get the information (www.fda.gov.foi). If your supplier hasn't been FDA inspected, find out why. If you discover that your tissue bank is an unaccredited ?partial supplier,' you may want to seek assurance that its suppliers meet FDA and/or CDC guidelines.

What's Being Done to Protect Patients? Here are two ways that the government and industry are trying to minimize allograft-associated infections: Increased federal oversight. The tissue bank industry will undergo a regulatory transformation similar to that of the blood bank industry, according to orthopedic surgeon Warren D. King. FDA has proposed a set of new regulations that will require tissue banks to maintain quality assurance programs; monitor manufacturing processes; validate all processes; follow specific procedures for inspecting, accepting, and rejecting tissues; and track tissues. Improved sterilization methods. The great challenge is to strike a balance between sterility and preserving graft integrity. The most common method - antimicrobial soaking - kills the vegetative forms of infectious bacteria but does not kill their spores. Ethylene oxide sterilization (ETO) and gamma irradiation are highly effective, but ETO can leave behind a chemical residue that may cause chronic synovitis, and irradiation can destroy collagen and weaken the graft. Fortunately, there are several potentially better sterilization methods on the horizon. One firm, Clearant, Inc., is taking its technology - which prevents collagen breakdown during irradiation - to FDA for approval.

3. Research your tissue bank's practices.
You may want to ask your supplier about its processing methodologies. For example:

• What is the time between donor death and tissue harvesting? AATB standards require harvesters to retrieve allograft tissue within the first 15 hours after death or, if the body is refrigerated within the first 12 hours, to harvest the tissue within the first 24 hours after death, according to AATB Chief Executive Officer Bob Rigney. The allograft implanted into a 23-year-old who died was procured 23.5 hours after death from a body refrigerated 19 hours after death, according to Dr. Kainer.
• What do you do to prevent bacteriostasis? Many processors place allograft tissue in an antimicrobial soak, take a section for analysis and then package the bulk of the tissue for distribution pending the result. The culture of the sample tissue should turn positive whenever detectable levels of vegetative forms of bacteria appear. The trouble is, while the antibiotic soak does not kill spores, it does kill vegetative forms as soon as they develop from spores. So, even a spore-laden allograft can produce a clean culture. This is known as bacteriostasis. In addition, Dr. Kainer notes that the test tissue may not be representative of the whole allograft because the antibiotic-antifungal solution may penetrate deeper into the smaller test sample than it does into the larger allograft. Dr. Kainer recommends that processors culture tissue before suspending it in antimicrobial solution, discarding all tissue with clostridia or other bowel flora and validating culture methods to ensure that residual antimicrobials/antifungals do not produce false-negative results for other types of bacteria.
• What are your donor selection criteria? Research shows that highly pathogenic organisms typically originate from the donor's GI or upper respiratory tract, and that allograft contamination from these pathogenic organisms is more common in donors who die from trauma or have positive blood cultures, according to Drs. King and Barbour. "The ideal graft donor is under the age of 40, has not had a terribly traumatic death involving stomach trauma or a lot of resuscitation, and has been refrigerated," notes Dr. King. "The tissue must also be harvested in the most sterile environment."

4. Perform your own cultures.
Culture all allograft specimens "out of the bag" for both aerobic and anaerobic bacteria, says Dr. King. "Although it adds expense, culturing should be standard practice," says Dr. King. "This gives us an opportunity to trace any bacterial infection to the source." It also lets the physician initiate antibiotic therapy early should the patient show signs of infection.

Dr. King reports a 10 to 15 percent "out-of-the-bag" contamination rate in his practice, but says the bacteria are almost always clinically inoffensive. However, for this reason and as a general precaution, he routinely prescribes a prophylactic, gram-positive antimicrobial regimen.

5. Follow good sterile practice.
Good sterile practice is a final and essential line of defense against allograft-associated infections. According to Dr. Eastlund, in two of the CDC reports investigated so far, there is no epidemiologic evidence to implicate pre-packaging allograft contamination. Rather, he says, the Pseudomonas aeruginosa infections that developed after ACL repair in these two cases may have resulted from contamination in the OR. "Just the simple act of moving an [opened] allograft from one sterile area to another increases the bacterial load from the environment," he notes. He advises following good aseptic technique when removing allografts from their containers, evaluating and updating methods of reprocessing arthroscopy equipment and being vigilant about general infection prevention.

See the big picture
Given that surgeons implant more than 750,000 allografts each year, the rate of associated infection appears extremely low. "These procedures have prevented more disease than they'll ever cause," says Dr. King, who has implanted more than 18,000 allografts and has seen just one allograft-related infection in his patients.

Nevertheless, experts agree that it pays to stay on guard, because just one infection can prove devastating to a young, active patient. "We need to make allografts better," says Dr. King, "and I think we can."

Contact Dianne Taylor at [email protected].