Diagnosis
Clinical symptoms observable four to eight days after joint replacement are the main indicators of immediate periprosthetic infection in the early stages. The usual symptoms include continued swelling of the operated area, wound dehiscence and purulent secretion. These symptoms, however, are not always manifest. Sometimes only slight discomfort in the operated leg or difficulties in rehabilitation are detected. With deep infections, superficial problems of wound healing, such as wound dehiscence, hematomas and seromas, are often seen.
In detecting early infections, laboratory data from CRP tests are very helpful. In normal wound healing, postoperatively increased CRP values peak between day three and five, reaching normal levels at about day ten. In infected cases, CRP levels tend to stay high, with an abnormal first course and later secondary increases.
The erythrocyte sedimentation rate's lag time about six days is longer than that of CRP; thus ESR investigation allows diagnosis of wound sepsis by the end of the second week at the earliest, whereas CRP provides useful information by the end of the first week.
Both ESR and CRP have a specificity and a sensitivity of about 90%. By contrast, counting leukocytes is unspecific and not particularly helpful. Other sophisticated indicators, such as Interleukin 6, Procalcitonin and the Interleukin 2 receptor, are quite expensive and provide no additional useful information.
Radiographs also are not helpful in detecting immediate infection, and in late infections they often lend only support. Bone resorption, as in osteolysis or periarticular ossifications, sometimes can be seen in X-rays, but in the event of a low grade infection particularly, X-rays are mostly normal. Computer tomography and nuclear magnetic resonance tomography do not detect periprosthetic infection well because of the metal artefacts. Szintigraphy cannot differentiate septic from aseptic loosening of the prosthesis. It is possible that leukocyte szintigraphy, in particular the 99 technetium Nanocolloid method, can provide useful information.
In our opinion, the most reliable method for detecting periprosthetic infection is preoperative aspiration of the joint fluid. This must be done under strictly sterile conditions. The specificity and sensitivity of this investigation, in our experience, is more than 95%. And we are mindful to consider an important detail when investigating the aspirated fluid: the number of bacteria is small initially, so the culture must stand for a minimum of ten days not a mere three days, as is the norm for blood cultures.
Antibiotics and bone cement
The first widely recognised application of the concept that elution from bone cement could serve as a source of antibiotic therapy in patients was reported by Buchholz and Engelbrecht in 1970 a time, in the early days of arthroplasty, when the rate of postoperative periprosthetic infection exceeded 10%. Antibiotics administered systemically turned out to be ineffective in defeating these infections because (as we later discovered) the antibiotic concentrations at the site of infection were insufficient to act on the bacteria causing the infection.
Buchholz and microbiologist Lodenkämper added several antibiotics (erythromycin, penicillin, tetracycline and others) to the bone cement and observed the rate and duration of elution. Some of these antibiotics, especially gentamicin, showed a very promising elution rate over an extended period of time.
Buchholz in 1977 published an infection frequency of 5% for 1161 total hip arthroplasties using bone cement without antibiotics. In contrast, the frequency of deep infections for 5600 hip prostheses using gentamicin-loaded cement was 0.2%. Other authors reported similar results. In fact, in every documented study since then, the infection rate of primary hip replacements using antibiotic-loaded acrylic bone cement has been significantly lower than when cement devoid of antibiotics is used, a finding that we have confirmed regularly. Consequently, since 1972 we have routinely used gentamicin-loaded bone cement in all primary implantations performed at our clinic .
One of the crucial elements of acrylic bone cement is PMMA, which allows retention of antibiotics at the site of infection and therefore administration of dosages that would otherwise produce toxic side effects. Diffusion is key to this application system. The transport of substances follows a gradient from the highest to the lowest concentration in a system, until the concentration is identical at all parts of that system. The time necessary to achieve this balance of concentration depends on the mobility of the molecules involved. It works best if the substance dissolves like sugar in a cup of tea. We learned this in school. What we probably did not learn is that diffusion is also possible in systems that are free of solvents. In such systems, the mobility of the molecules is simply slow, resulting in slow transport of the substance. Physicists call this a mass of diffusion.
Lindner (1981) and later Low and co-workers (1986) showed that the transport of antimicrobial agents in PMMA bone cement follows Fick's law, proving that it is indeed a type of diffusion albeit slow because of the absence of solvents taking place in the bone cement and transporting antibiotics from the inside of the bone cement to the surface. Under the skin, humans are like aquariums, providing the surrounding water in which the antibiotics of the cement are able to diffuse rapidly.
When the antibiotics reach the surface of the bone cement, their concentration diminishes with the third potency of the distance by diffusion in the blood stream. This is why high concentrations of antibiotics are delivered to the surface of the bone cement around the prosthesis, where needed, while the systemic concentrations remain low, resulting in a low incidence of side effects.
It has been demonstrated in vitro that the total time of delivery is much longer than the period of effective concentrations in the wound discharge, meaning that the antibiotics act at the surface for a prolonged period and are thus able to prevent colonisation of the surface. This effect may last for years, as demonstrated with gentamicin by Josefson in a controlled study in Sweden. The prophylactic effect alone lasts for about five years.
There are rules that must be followed when adding antibiotics to bone cement in the operating room. The antibiotics must be used only in powder form, and the mixture should be as homogenous as possible. Hand mixing is usually employed. An indiscriminate use of antibiotics in the bone cement must be cautioned against, for if the wrong mixture or amount of antibiotics is used, the effectiveness of the concept can be greatly marginalised.
Under no circumstances should aqueous solutions be mixed with the bone cement, as these solutions dramatically weaken the cement. The antibiotics to be mixed in the cement must remain stable at the temperature occurring during polymerisation of the cement.
The antibiotic concentration at the cement surface is meant to have an absolutely bactericidal effect. The proportion of antibiotics to the cement in which they are mixed should not exceed 10%; amounts higher than this result in mechanical weakening of the cement and may lead to early loosening.
A recently completed clinical study in which we investigated the outcome of one-stage exchange operations at the hip with reimplantation of a new prosthesis using an industrially manufactured bone cement containing one gram of clindamycin and one gram of gentamicin per 40 grams cement produced the following results:
The wound fluid, where the antibiotic effect is needed, contained extremely high concentrations of clindamycin and gentamicin. The concentration levels in the serum ranged from at least 100 times lower to undetectable levels, which resulted in a low incidence of systemic side effects. No persistence or recurrence of periprosthetic infection was observed during a period of six years after revision. Only in one case was there aseptic loosening of the cup after five years.
When analysed according to Merle d'Aubigne's score, the clinical results showed an improvement for patients in pain, function an mobility. In no patients were side effects reported.
In one-stage septic prosthesis exchange, radical resection of infected tissue and removal of all foreign material is essential, and antibiotics must be considered an indispensable contributor to the success of the operation The addition of antibiotics, though, can work only in combination with meticulous surgery. Surgery is the therapy; antibiotics are a supplement to the surgical procedure.
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