PROSTHETIC JOINT INFECTIONS AND ANTIBIOTIC-LOADED CEMENT
Deep infection may complicate nearly 1% of total hip45 and 2% of total knee arthroplasties.46 Kurtz et al4,6 have projected that by 2030, infection will be the cause of two-thirds of the estimated 268,000 revision total knee arthroplasties and about half of the estimated 96,700 revision total hip arthroplasties.
The most common method of treating a chronically infected replacement joint is a 2-stage procedure.5 First, the prosthesis is removed, all infected bone and soft tissue is debrided, and an antibiotic-loaded cement spacer is implanted. Systemic antibiotics are given concurrently, typically for about 6 weeks. After the infection is brought under control, perhaps 2 to 3 months later, the spacer is removed and a new joint is implanted with antibiotic-loaded cement. A 1-stage procedure may be an option in selected cases and would obviate the need for an antibiotic-loaded cement spacer.47,48
Of obvious relevance to development of acute kidney injury is the choice and amount of antibiotics embedded in the cement used for spacers and in implantation. Very high antibiotic levels are achieved within the joint space, usually with little systemic absorption, although significant systemic exposure has been documented in some cases.
The polymethylmethacrylate cement used for these purposes comes in 40-g bags. Multiple bags are typically required per joint, perhaps 2 to 4.49
The rate of elution of antibiotics is determined by several factors, including surface area, porosity, and the number of antibiotics. In general, elution is greatest early on, with exponential decline lasting perhaps 1 week, followed by slow, sustained release over weeks to months.50 However, several in vitro studies have indicated that only about 5%50,51 of the total antibiotic actually elutes over time.
Initially, multiple antibiotic-laden cement beads were used to fill the joint space, but this significantly limited function and mobility.52 Now, cement spacers are used, and they can be nonarticulating or articulating for maximal joint mobility.53 Although much greater antibiotic elution occurs from beads due to their high surface area-to-volume ratio, spacers still provide an adequate dose.
ANTIBIOTIC-LOADED CEMENT: DOSAGE AND ELUTION CHARACTERISTICS
Antibiotic-loaded cement can be either low-dose or high-dose.
Low-dose cement typically consists of 0.5 to 1.0 g of antibiotic per 40-g bag of cement, usually an aminoglycoside (gentamicin or tobramycin) or vancomycin, and can be purchased premixed by the manufacturer. Such cement is only used prophylactically with primary total joint arthroplasty or revision for aseptic reasons, a practice common in Europe but less so in the United States. Some American authors propose antibiotic-loaded cement prophylaxis for patients at high risk, eg, those with immunosuppression, inflammatory cause of arthritis, or diabetes.54
Vrabec et al,55 in a study of low-dose tobramycin-loaded cement used for primary total knee arthroplasty, found a peak median intra-articular tobramycin concentration of 32 mg/L at 6 hours, declining to 6 mg/L at 48 hours with all serum levels 0.3 mg/L or less (unmeasureable) at similar time points.
Sterling et al,56 studying primary total hip arthroplasties with low-dose tobramycin-loaded cement, found mean levels in drainage fluid of 103 mg/L at 6 hours, declining to 15 mg/L at 48 hours. Serum levels peaked at 0.94 mg/L at 3 hours, declining to 0.2 mg/L by 48 hours.
Although most of the antibiotic elution occurs early (within the first week), antibiotic can be found in joint aspirates up to 20 years later.57 We are unaware of any well-documented cases of acute kidney injury ascribable to low-dose antibiotic-loaded cement used prophylactically. One case report making this assertion did not determine serum levels of aminoglycoside.58
High-dose antibiotic-loaded cement typically contains about 4 to 8 g of antibiotic per 40-g bag of cement and is used in the treatment of prosthetic joint infection to form the spacers. The antibiotic must be mixed into the cement powder by the surgeon in the operating room.
There is no standard combination or dosage. The choice of antibiotic can be tailored to the infecting organism if known. Otherwise, gram-positive organisms are most common, and vancomycin and aminoglycosides are often used together. This particular combination will enhance the elution of both antibiotics when studied in vitro, a process termed “passive opportunism.”59 Other antibiotics in use include aztreonam, piperacillin, teicoplanin, fluoroquinolones, cephalosporins, and daptomycin, among others.
About 8 g of antibiotic total per 40-g bag is the maximum to allow easy molding.52 As an example, this may include 4 g of vancomycin and 3.6 g of tobramycin per 40 g. Given that 3 to 4 such bags are often used per joint, there is significant risk of systemic exposure.
Kalil et al60 studied 8 patients who received high-dose tobramycin-loaded cement to treat periprosthetic joint infections of the hip or knee and found that 7 had detectable serum levels (mean 0.84 mg/L, highest 2.0 mg/L), including 1 with a level of 0.9 mg/L on day 38; 4 of these 8 developed acute kidney injury by AKIN criteria, although other risk factors for acute kidney injury existed. Nearly all had concomitant vancomycin (3 to 8 g) added to the cement as well.
Hsieh et al61 studied 46 patients with infected total hip arthroplasties treated with high-dose antibiotic-loaded cement spacers (vancomycin 4 g and aztreonam 4 g per 40-g bag) and found vancomycin levels in joint drainage higher than 1,500 mg/L on day 1, decreasing to 571 mg/L on day 7; serum levels were low (range 0.1–1.6 mg/L at 24 hours), falling to undetectable by 72 hours.