Ilker Uçkay
Daniel P. Lew
Introduction
Over the past decades, joint replacement has become one of the most common types of prosthetic surgery because of its success in restoring function to disabled arthritic persons [1,2,3,4]. More than 200,000 total hip replacements and millions of implants are implemented in the United States each year, and it is estimated that total knee replacement is performed as frequently as total hip replacement [2,5]. The safety and biocompatibility of these devices are good, and only 10% of all patients experience complications during their lifetime. Second to loosening of the prosthesis, infection is the most common complication of orthopedic implant surgery. In the United States, it is estimated that 4% of all implants become infected [5]. The rate of infection after total hip arthroplasty in early surgical series was initially unacceptably high. In Charnley's early series, the infection rate was 7%. Air filtration and prophylactic antibiotics reduced the rate of infection to 0.6% in a later series [6]. At present, the lifetime infection rate is thought to be 0.5–1.0% for total hip arthroplasty, 0.5–2.0% for knee, and <1% for shoulder replacement [2,3,7]. Even though the incidence has fallen steadily, the absolute number is rising because of the increase in the number of orthopedic operations performed. The economic burden to healthcare-associated infection (HAI) with septic prosthetic joints is very high. The cost to treat patients with hip or knee prosthetic osteomyelitis, respectively, has been calculated to be 5.3- and 7.2-fold higher than the primary operations [8].
Musculoskeletal Allografts
The use of human allografts in orthopedic surgery has gained momentum. In 2001, approximately 875,000 musculoskeletal allografts were distributed by U.S. tissue banks compared to 350,000 in 1990 [9]. Processed tissue allografts are not necessarily sterile and may result in viral or bacterial infections. Tomford et al. reported a 5% and a 4% incidence of infection related to the use of allografts in patients who had surgery for bone tumor and revision hip arthroplasty, respectively [10]. Other studies have demonstrated infection rates as high as 12.2% when banked allografts are used for reconstructive surgery [11]. Mankin et al. found in a series of 945 patients who received cadaveric allografts 7.9% primary infections and an additional 4.9% infections related to re-operations [12]. Cadaveric allografts have been shown to be contaminated at a rate of 27% in the study by Ibrahim et al. [13] and other studies.
Pathogenesis
According to a proposed classification in the 1970s, prosthetic joint infections can be classified according to the time of onset of infection [3]. By this classification, acute infection (stage 1) is defined as occurring within six months of surgery (≤40% of total infections); they are often evident within the first few weeks. The mechanism involved is the introduction of microorganisms during the operative procedure. Staphylococcus aureus is the classic pathogen. The freshly implanted biomaterial is highly susceptible to infection. The majority of joint infections is acquired in the
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operating room (OR). Reasons for that are the efficacy of perioperative antibiotic prophylaxis, laminar flow in the OR and the similarity of skin flora and the pathogens that cause prosthesis infections. Moreover, during the early postimplantation period, when superficial infections can develop, the fascial layers have not healed, and the deep, periprosthetic tissue is not protected by the usual physical barriers. Any factor or event that delays wound healing increases the risk of infection: ischemic necrosis, hematomas, and, more directly, wound sepsis or suture abscesses [14,15].
Subacute infection (stage 2) develops within 2 years of operation (≤45% of total infections). They are due to low-virulence microorganisms included during surgery (e.g., coagulase-negative staphylococci). Late infections (stage 3) emerge after 2 years of pain-free mobility (≥15% of total infections) and are mostly attributed to hematogenous seeding with selective persistence of the microorganisms in the joint. Dentogingival infections and manipulations, although exceptional, have been described as causes of viridans group streptococcal and anaerobic infections of prostheses. Pyogenic skin processes can cause staphylococcal (S. aureus and S. epidermidis) and streptococcal infections of replaced joints. Genitourinary and gastrointestinal tract surgeries or infections are associated with gram-negative bacillary, enterococcal, and anaerobic infections of prostheses. The use of antibiotic prophylaxis in grade III open fracture procedures has substantially decreased the frequency of bone infections and subsequent surgery.
Infecting Microorganisms
Virtually any microorganism can cause prosthetic joint infection. A single pathogen can be identified in only about two-thirds of patients [16]. The predominant microorganisms are staphylococcal species (~50% in several series), evenly divided between S. epidermidis and S. aureus. Aerobic streptococci are responsible for a significant group of infections (between 10–20% in different series), followed by Gram-positive organisms ordinarily considered culture “contaminants,” such as Corynebacteria spp., Propionibacteria spp., andBacillus spp. Gram-negative aerobic bacilli have been identified in some series in ≤25% of patients, and anaerobes usually do not account for >10% of all pathogens. In up to 10% of patients, no organisms can be detected. Among allografts, Gram-positive bacteria are equally the most frequent infecting pathogens [13]. Recently, organisms such as Clostridiumspp. have become a concern. Malinin et al. showed that among 795 donors of allografts in the United States, 8.1% of donor blood, marrow, or donor musculoskeletal samples grew clostridia, mainly C. sordellii [17]. The pathogenicity of this organism is related to its ability to produce lethal factors, which cause local necrosis, edema, and hemorrhage. This said, it should not be forgotten that Clostridia spp. may be involved not only in allograft infections but also in more classical prosthetic joint infections [18,19].
Role of the Foreign Body and Biofilms
Attachment of bacteria to a prosthetic joint is a critical first step in the pathogenesis of virtually all foreign body–associated infections. A foreign body reduces the inoculum of S. aureus required to induce subcutaneous infection from >100,000-fold to as little as 100 colony-forming units [4,20]. In addition, the interaction of neutrophils with the foreign body can induce a neutrophil defect that may enhance the susceptibility to infection [21]. Ultra-high molecular weight polyethylene particles, emitted by prosthesis material, seem to add to the inhibition of the neutrophil antibacterial activity [22]. Bacteria deep within the biofilm that are metabolically inactive or in various stages of dormancy are protected from host defenses such as phagocytes and are highly resistant to antimicrobial agents [23]. The micro-environment within a biofilm may also adversely affect diffusion of antimicrobial agents. Soon after a biofilm is established, the susceptibility of bacteria to antimicrobial agents considerably decreases. With an infection of >1 month duration, it has been postulated that the biofilm has progressed to such a degree that cure with prosthetic retention is less achievable than with removal.
Diagnosis
Clinical Presentation
There are no uniform clinical criteria for the diagnosis of prosthetic joint infections. Most patients experience a long, indolent course of infection characterized by steadily increasing joint pain and the occasional formation of cutaneous draining sinuses. A minority of patients has an acute fulminant illness associated with high fever, severe joint pain, local swelling, and erythema. Patients with late-onset infections due to hematogenous seeding can present with acute onset of symptoms in one or several previously well-functioning joints. The pattern of clinical presentation is determined largely by the nature of the infecting microorganism (i.e., the symptoms are more prominent in S. aureus infections compared with S. epidermidis). Infection must be differentiated from aseptic mechanical problems. Constant joint pain suggests infection whereas mechanical loosening commonly causes pain only with motion and weight bearing. Nevertheless, often it is difficult to differentiate delayed-onset infection from aseptic joint loosening of hip or knee prostheses.
Erythrocyte Sedimentation Rate (ESR) and C-Reactive Protein (CRP) Levels
Persistent elevation of the ESR suggests infection but is neither very sensitive (87%) nor very specific (47%) because
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it may be due to many other causes [24]. The same is true for leucocytosis or CRP. Combined measurement of the CRP and ESR seems to have an acceptable negative predictive value although it does not completely rule out a prosthetic joint infection. These two parameters also are more appropriate to measure as follow-up during therapy than for diagnosis. The role of pro-Calcitonin in nonsystemic prosthetic infections needs further evaluation, although it seems to be useful at least in pediatric osteomyelitis [25].
Radiology
A plain radiograph can display abnormal lucencies (>2 mm in width) at the bone-cement interface, changes in the position of prosthetic components, cement fractures, periosteal reaction, and motion of components. Periosteal new bone formation suggests infection but is infrequently present because it is the presence of fistula between the joint and soft tissue. When both the distal and proximal components of a prosthetic joint demonstrate radiographic abnormalities, infection is more likely than simple mechanical loosening. In the report of Bernard et al, the sensitivity and the specificity of radiographic anomalies were 73% and 76%, respectively [24]. Magnetic resonance imaging or computed tomography techniques for evaluating prosthetic joints for infection are of little help because metal present in prostheses causes interference. Radioisotopic scans demonstrate increased uptake in areas of bone with enhanced blood supply or increased metabolic activity, but this does not help to diagnose true infection because increased uptake routinely is seen around normal prostheses for several months after arthroplasty. Smith et al. investigated the usefulness of bone scintigraphy between knee replacement surgery and onset of knee pain of 3 years. The pattern of isotope uptake in the abnormal studies was not specific enough to reliably differentiate aseptic from septic loosening [26]. This result was confirmed in a report of 144 patients who underwent revision hip arthroplasty; bone-gallium imaging offered no additional advantage in diagnosis over hip aspiration [27]. According to Bernard, sensitivity and specificity of bone scintigraphy was at best 76% each [24]. Only limited data are available for positron emission tomography (PET). In a report of 35 patients with painful hip replacements, PET scan performed similarly to scintigraphy and was less sensitive and more specific than conventional bone radiography [28]. In conclusion, a normal bone scintigraphy is generally useful to exclude the need for surgical intervention aimed at correcting joint loosening or infection [26].
Joint Aspiration
Laboratory tests and imaging studies may be of value but are usually not diagnostic. As a result, the diagnosis of prosthetic joint infections always requires obtaining samples of joint fluid or tissue [29,30,31]. The most important step is to isolate the offending organisms so that the appropriate antimicrobial therapy can be chosen. The importance of the identification of the pathogen cannot be overemphasized. Alternatively, isolation can be achieved by blood culture, generally only in hematogenous osteomyelitis, or by direct biopsy from the involved bone because the joint fluid aspirate may be falsely negative or positive (the latter because of contamination with skin organisms). Whenever biopsy or aspiration is done, the samples should be processed for aerobic and anaerobic cultures. Samples for mycobacterial and fungal cultures should be taken and processed if commonly cultured microorganisms are not present and if the clinical features are compatible. Often culture growth time has to be extended beyond the standard incubation period of 5 days. Tissue specimens also should be submitted for histopathologic study. Special staining techniques may reflect unusual or slowly growing microorganisms.
Hip aspiration arthrography had a sensitivity of 79% for diagnosing the infection and a specificity of 100% [1]. Trampuz et al. reported that a synovial fluid leukocyte differential of >65% neutrophils has a 97% sensitivity and 98% specificity for diagnosis of prosthetic knee infection [31]. A negative Gram's stain is of no value because the reported sensitivity is as low as 12–19% in perioperative specimens.
Histopathologic examination showing acute inflammation (a high number of neutrophils per microscopic field) has a sensitivity of >80% and specificity of >90% [32]. When intra-articular fluid is difficult to obtain, irrigation with sterile normal saline can provide the necessary fluid for culture. However, such cultures may be difficult to interpret if coagulase-negative staphylococci or common contaminants are recovered. When initial cultures indicate a relatively avirulent microorganism (S. epidermidis, corynebacteria, propionibacteria, or Bacillus spp.), a second aspiration should be considered to confirm the bacteriologic diagnosis and to eliminate the possibility of contamination. Semiquantitative cultures may be useful to distinguish between infection and colonization for indolent microorganisms. Material taken from an open sinus or from joint fluid tract by swabbing will give misleading results because the isolates may include nonpathogenic microorganisms that are colonizing the site [4].
Cultures obtained at operation are diagnostic if the patient has not received antimicrobial therapy before the procedure whereas routine cultures performed during clean orthopedic implant insertion procedure are not useful for predicting postoperative infection [33].
Treatment
Treatment of prosthetic joint infections is not standardized due to the variable clinical presentations and the lack of data from randomized, controlled trials. Treatment usually involves both medical and surgical measures [3], depending on the cause and timing of the infection and the condition
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of the host. Treatment should begin immediately after the onset of symptoms because organisms within the biofilm are more resistant to therapy; as a result, antimicrobial therapy often is unsuccessful unless the biofilm is physically disrupted or removed by surgical debridement.
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TABLE 39-1 |
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Single-agent chemotherapy usually is adequate for intravenous treatment of prosthetic joint infection. Antibiotics should be chosen based on the susceptibility of the isolated microorganism, bone penetration and, in later stage, the best oral bioavailability. As a general principle, antibiotics should be given parenterally for 2 to 4 weeks, which may be followed by several weeks to months of oral therapy. The conventional choices of antimicrobial agents for the most commonly encountered microorganisms in infections of skeletal prostheses are given in Table 39-1.
Antibiotic Therapy without Prosthesis Removal
Antibiotic treatment alone without the removal of the prosthesis is not considered standard therapy for prosthetic joint infection and has been associated with a failure rate of >90% [3,4]. However, in selected patients, antibiotic treatment might be an option under the condition that at least one early and careful concomitant surgical debridement is performed and that the prosthesis is not loose. By definition, this approach is possible only in so-called early onset infections and can be curative in a high proportion of cases [34]. There is a greater chance of success when microorganisms are of low virulence and highly susceptible to IV and orally administered antibiotics. Open debridement is necessary in most patients with acute infected hip and knee prostheses.
In a recent review, Zimmerli et al. have published an algorithm [3] showing that debridement with prosthesis retention supplemented by irrigation and antibiotic treatment with a regimen active in biofilms (containing rifampin for staphylococci and a quinolone for gram-negative pathogens) for 3 to 6 months is adequate for early onset or hematogenous infections with symptoms <3 weeks and stable implant under the condition that there are no difficult to treat pathogens, such as MRSA.
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The exact duration of antibiotic therapy after debridement is somewhat arbitrary with suggestions ranging from 3 to 6 months (for knee joint replacement), particularly when oral antibiotics are used [3,37]. However, the majority of patients presenting with a chronic or subacute infection associated with prosthesis loosening will not be cured unless the prosthesis is removed. In patients in whom removal of the prosthesis is not feasible (owing to medical and/or surgical contraindication or the patient's refusal to undergo surgery) and the patient tolerates an active drug for prolonged periods, suppressive antimicrobial therapy may be attempted. Careful monitoring is important because of the danger of extension of the septic process, progressive bone resorption, and side effects of a chronic oral antibiotic treatment.
Antibiotic Therapy with Prosthesis Removal and Reimplantation
To achieve a microbiologic cure, it is almost always necessary to remove the prosthesis and all associated cement and completely debride devitalized tissue and bone. Duration of concomitant intravenous antibiotic therapy is at least 6 weeks. Upon removal of the prosthesis, there are several options; they include resection arthroplasty without reimplantation, arthrodesis, or one-stage or two-stage reimplantation of a new prosthesis.
In the absence of a prospective randomized study with prolonged follow-up, it is difficult at present to recommend one-over two-stage arthroplasty [3,4,35]. For hip prosthesis, analysis of published studies does not show any advantage of the one-stage exchange arthroplasty with or without antibiotic cement compared to the two-stage approach. All reports have been retrospective studies, and only a few described the proportion of patients with infected arthroplasties who received one-stage exchange arthroplasty and adequately contrasted their clinical features with patients who received alternative treatments. With one-stage exchange arthroplasty, the infected components are excised, surgical debridement is performed, and a new prosthesis is immediately put in place under antibiotic coverage. It may be suitable in highly selected hip prosthesis patients who have satisfactory soft tissue, no severe coexisting illnesses, no fistula, no need for bone graft, and infection with organisms that are highly susceptible to antimicrobial drugs [35]. Zimmerli et al. believe that one-stage hip replacement arthroplasty is successful in >80% of carefully selected patients [3].
The two-stage approach requires careful surgical removal of all foreign body material and infected tissue followed by prolonged parenteral and oral therapy [3,4]. The advantages of two-stage hip reimplantation arthroplasty are that it allows for additional debridement and optimization of the choice of antibiotic and duration of therapy for more virulent pathogens. The ideal pause between surgeries is not well established but frequently results in considerable economic hardship and morbidity [35]. The shortest duration of antibiotic therapy would be 6 weeks. The disadvantage is that, as a result of scarring, the second intervention is more difficult to perform and can lead to a second perioperative morbidity and mortality risk for patients with advanced age and serious comorbidities. In patients who have experienced extensive bone loss, a third stage, consisting of bone grafting, is required between resection and reimplantation. Reported success rates of >90% are achieved with two-stage replacement arthroplasty for infected hip prostheses with the interim use of antibiotic-loaded cement [36]. Most U.S. centers use two-stage arthroplasty, whereas the one-stage approach in more commonly performed in Europe with a variable intermediate period between excision and reimplantation [3].
Similar results have been reported in patients with infected knee prostheses. Among a total of 1,143 infections treated with one-stage exchange arthroplasty and with antibiotic-impregnated cement, 915 did not recur (80% success rate). The success rate of two-stage arthroplasty (with or without antibiotic-impregnated cement) was slightly higher (85%) among a total of 262 patients analyzed. Most surgeons favor the delayed two-stage exchange arthroplasty, but this position does not reflect a large body of evidence [37]. However, with the two-stage procedure, patients are at risk of scarring, with resultant loss of range of motion after resection, and, thus, the period of parenteral antimicrobial therapy before re-implantation is not prolonged beyond 6 weeks to preserve joint function. For other prosthetic joints (shoulder, elbow), two-stage exchange with the use of antibiotic-impregnated cement is preferred, although this procedure is costly and time consuming.
Close monitoring and normalization of clinical and inflammatory parameters are mandatory. Prosthetic joint infections due to M. tuberculosis sometimes can be cured without joint removal if the infection is recognized early [38]. Fungal prosthetic joint infections are difficult to cure with medical therapy alone. As a result, most such patients require prosthesis removal and arthrodesis to resolve their infections [39].
Antibiotic-Impregnated Cement
Antibiotic-impregnated cement is widely used for prophylaxis and therapy of implant surgery infections but still remains controversial [2,40]. Many antibiotics appear to be released from the cement in potentially efficacious amounts, but the duration of time over which these antibiotics continue to be released is less certain. Moreover, the advantage appears minimal in two-stage procedures. Thus, a lowering of the infection rate often is difficult to attribute to the use of antibiotic-impregnated cement alone. It also is worth noting that gentamicin, the most widely
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used compound, is not the agent of choice to prevent or treat staphylococcal infections and may lead to local development of S. aureus small colony variants [41].
Musculoskeletal Allografts
There are no guidelines or consensus for the duration of concomitant antibiotic therapy for musculoskeletal allograft infections.
Risk Factors and Prevention
General Preventive Measures
Today, well-established risk factors for surgical site infections (SSIs) in the literature (mostly for cardiovascular surgery) include insufficient perioperative glycemic control, prolonged hospitalization before surgery, malnutrition, preioperative hair shaving instead of clipping, timing of hair removal, lack of perioperative normothermia, concomitant immunosuppressive therapy, inexperienced surgical team, long operating time, lack of a OR with laminar airflow, lack of compliance with hand hygiene, lack of surveillance, feedback of results and infection control policy for SSIs, and appropriate antibiotic prophylaxis. All these are potential and modifiable quality indicators to reduce the incidence of SSIs.
Preventive Measures and Risks for Prosthesis Infections
A case-control study compared 462 first episodes of prosthetic hip or knee infection with controls matched for age, gender, site of prosthesis, and the date of surgery. The major risk factor was an SSI at a site other than the prosthesis (odds ratio 35.9) [42]. Another study found among 4,240 total hip, knee, and elbow arthroplasty procedures the following risk factors: rheumatoid arthritis, perioperative nonarticular infections, prior infection of the joint or adjacent bone, prior surgery on the joint, prolonged duration of surgery, higher number of OR personnel, postoperative bleeding or hematoma formation, and advanced age [43].
Benefits of Antibiotic Prophylaxis and Ultraclean Air Systems
Between 1970 and 1980, several studies suggested that antimicrobial prophylaxis reduces the incidence of deep incisional SSI after total joint replacement. Hill et al. reported that prophylaxis with cefazolin significantly reduced the SSI incidence compared with a placebo [44]. However, when the results were examined according to the type of OR used, differences were found to be significant only among patients whose surgery was performed in a conventional setting. In a “hypersterile” environment, the rates of SSI were the same for cefazolin-treated and placebo-treated groups. Thus, antibiotic prophylaxis and ultraclean air systems appear to be independent factors in limiting the rate of foreign body infection. Cefazolin has generally been used for prophylaxis in total joint replacement and other surgery because of its greater intrinsic activity against staphylococci, narrower side effect profile, and lower cost, but many reports in the surgical literature also have evaluated the newer cephalosporins. For those with skin colonization with methicillin-resistant S. aureus (MRSA), vancomycin prophylaxis may be warranted. On the other hand, despite high prevalence of MRSA SSIs within an institution, a meta-analysis failed to show a benefit of vancomycin compared to beta-lactams in cardiac surgery [45]. Contrary to the cardiovascular surgical literature, topical or nasal mupirocin prophylaxis before orthopedic surgery has not been proven efficacious.
Several studies have found that administration of antibiotics for 12–24 hours is as effective as prolonging antibiotic therapy for several days [46]. Patients receiving the prophylaxis within a 2-hour “window” before the initial incision have lower rates of SSI than patients receiving the antibiotic either too early or postoperatively [47].
Some experimental evidence suggests that there is a risk of SSI of joint implants in the context of bacteremia, especially in the early postoperative period. There also is clear evidence that hematogenous infection of prosthetic joints sometimes stems from overt infections elsewhere in the body, particularly those of the urinary tract or the skin. Thus, vigorous treatment of infection elsewhere in the body is required before total joint replacement. The situation with regard to dental procedures is less clear. Analysis of a large number of patients indicates that the incidence of late-stage prosthetic joint infections associated with dental treatment is low (29 to 68 episodes per 106 dental visits) [48]. Accordingly, the American Dental Association has published statements that prophylaxis is not mandatory during dental procedure, but it should be considered in patients with increased risk, such as immunocompromised patients, and within one year after implantation. Treatment of severe periodontal disease and abscesses of the teeth and gums, in the presence of a foreign body, certainly requires administration of systemic antibiotics before orthopedic implant surgery [16].
Prophylaxis of Musculoskeletal Allograft Infections
After the death from Clostridium sordellii sepsis of a 23-year-old, otherwise healthy man who had received a contaminated allograft for his knee, the Centers for Disease Control and Prevention (CDC) reported in their investigation 0.12% infections among patients who received sports-medicine tissues and 0.36% among those who received
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femoral condyles in particular. Almost all Clostridium spp. infections were traced back to one single tissue bank [9]. Certainly, precautions are taken according to regional and national guidelines to minimize cross-infection of potential recipients. According to British procedures, procurement usually is performed under aseptic techniques and in an OR. The cadavers are draped and the skin is decontaminated with 10% iodine solution. The allografts are taken from the cadavers and passed to a second person working at a separate table. They are washed in normal saline and stripped of their soft tissue, swabbed over the entire surface for aerobic and anaerobic culture, and then placed into broth. Finally, the allografts are wrapped in sterile towels and plastic bags and are stored at -80°C [13]. If the time interval between death and retrieval is >24 hours or when culture results from blood or bone turn out to be positive, bone allografts are furthermore gamma irradiated or discarded. It has to be mentioned, however, that high doses of gamma irradiation may adversely effect the properties of the allografts [9] and that discarding contaminated bone would result in a wastage of resources in the graft banks where there is a shortage of donors, and infection following the implantation of bone allograft is a serious complication.
Despite these precautions, aseptic processing of tissue minimizes but does not eliminate bacterial contamination of spores, especially in tissue that is heavily contaminated at the time of recovery. Current regulations do not require tissue banks to eliminate bacteria present on tissues at the time of recovery or to use processing methods that guarantee tissue sterility. The main risk factor for contamination seems to be increased time between death and tissue excision.
In the CDC investigation mentioned earlier, there were several “system failures” leading to the epidemic of Clostridial spp. allograft infections: First, implanted tissues were not processed using methods that achieved sterility or that were sporicidal. Second, no tissues were cultured before being exposed to antimicrobial agents. Third, evidence ofClostridium spp. or bowel flora at other anatomical sites or reports of infections in other allograft recipients were not used as criteria for determining the suitability of donor tissues for transplantation [9]. The contamination of the allografts with Clostridium spp. is thought to be via hematogenous route of a donor because the interval between the donor's death and refrigeration of the body exceeded the limit recommended by voluntary industry standards (American Association of Tissue Banks [AATB]).
Sterilization methods that do not adversely affect the functioning of transplanted tissue would be best. Improved guidelines for tissue processing and testing, together with monitoring of allograft-associated adverse events, should enhance tissue-transplantation safety. The time interval between death and procurement should be kept as short as possible. The European Association of Musculoskeletal Transplantation (EAMST) and AATB recommend, for example, that harvesting of bone allograft should take place between 12 and 24 hours after death [49]. Finally physicians should have a high index of suspicion because relying on the results of postprocessing cultures alone to identify and discard tissues potentially contaminated with Clostridium spp. spores or other bacterial, fungal, or viral contamination is problematic. Recently, because of the underrecognition of allograft-associated infections and the increasing reports of such infections in the United States, the Food and Drug Administration has initiated a reporting system to better determine the extent of these infections.
References
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