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Antibiotic-Loaded Cement in Total Hip Replacement: Current Indications, Efficacy, and Complications

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Abstract

Antibiotic-loaded bone cement has been used since the1960s, and its advantages in the treatment of existing prosthetic infections have been repeatedly demonstrated. Care should be taken to match the antibiotic to the infecting organism, and cement intended for long-term prosthetic fixation should not contain >2 g of antibiotic powder per 80 g of polymethylmethacrylate. The use of antibiotic-loaded bone cement for prophylaxis against infection is controversial and should be used on an individual risk-benefit basis for patient groups at highest risk for development of deep infection.

Polymethylmethacrylate (PMMA), the predominant structural element in bone cement, was first synthesized in 1902 by Otto Rohn, MD. Sir John Charnley pioneered the use of PMMA in 1958 to fix hip implants. Cements specifically for orthopedic applications were manufactured in the 1960s (eg, Simplex P [Howmedica, UK] in 1962, CMW 1 [DePuy, Leeds, UK] in 1960, and Palacos [Heraeus Kulzer GmbH & Co. KG, Wehrheim, Germany] in 1967).

In 1969, Buchholz et al^1-3 introduced the technique of combining antibiotics with bone cement. Palacos bone cement-containing gentamicin powder was introduced as a commercial product in 1970. CMW bone cement containing gentamicin was introduced in 1990. Surgical Simplex P, which contains the antibiotic tobramycin (Howmedica, UK), was commercially released in 2002.

Although antibiotic bone cement is frequently used in the treatment of infected joint arthroplasties, its use for prophylaxis against bacterial infection is less prevalent. A literature review of 1299 primary exchange revisions revealed that 99% of infected total hip arthroplasty surgeries were performed with antibiotic bone cement.⁴ The survey of antibiotic cement use in the United States by Heck et al,⁵ revealed that for revision of an infected joint, 81%-85% of surgeons used antibiotic cement more than two thirds of the time. The National Study of Primary Hip Replacement Outcome in Britain revealed that 69% of the surgeon respondents used cement containing antibiotics for prophylaxis in primary total hip replacements.

The Scandinavian Joint Registries report prophylactic use of antibiotic cement in 95% of revision hip or knee arthroplasties, and a variation in primary joint replacement (48% in Norway, 85% in Sweden). Usage in the United States was surveyed by Heck et al⁵ in 1995. Of the 1015 surgeon responses from across the country, 56% used antibiotic cement in their practices. Of those, however, >90% used antibiotic-impregnated cement as prophylaxis in primary arthroplasty of previously infected joints.

For aseptic revisions of hip or knee arthroplasty, 67% of respondents used antibiotic cement, but on less than one third of patients. For routine primary total joint replacement, however, 11% of respondents regularly used antibiotic bone cement. Fish et al⁶ surveyed 338 American hospital pharmacists in 1992. They found that antibiotic-loaded cement was used in urban settings, particularly when hospitals were affiliated with training programs. Tobramycin was the incorporated antibiotic in 75% of patients, gentamicin in 17% of patients, and cefazolin in 11% of patients.

Efficacy of Antibiotic-Loaded Cement

Treatment of Established Prosthetic Infections
The rationale for antibiotic-loaded cement is the delivery of increased tissue levels of antibiotic without systemic toxicity and an elution profile that continues to provide bacteriocidal levels for an extended period (ie, up to 4 months).⁷ The advantages of antibiotic-loaded cement for patients with established prosthetic infection have been well documented. Hanssen et al⁸ showed a significant decrease in recurrent infection (ie, from 28% to 5% of patients) and an improvement in outcome with the use of antibiotic cement for a one-stage exchange in an infected total knee replacement.

Buchholz�s⁹ review in 1981 of 583 infected total hip replacements showed a 77% success rate in single-stage revision using antibiotic bone cement (Palacos cement containing 500 mg of gentamicin per 40 g of cement) without the use of systemic antibiotics, which increased the success rate to 90% with concomitant use of systemic antibiotics. Raut�s¹⁰ review of 183 patients who underwent one-stage treatments of infected total hip replacement showed a success rate of 84%. Jackson�s and Schmalzried�s⁴ review of 1900 infected total hip replacements treated with a one-stage revision revealed a cumulative success rate of 83% with antibiotic-impregnated bone cement, although no control group was mentioned.

In two-stage revisions for infected joint replacements, the success rate as reported is slightly higher. Lieberman et al¹¹ reported a 91% success rate with two-stage procedures for infected hip arthroplasty. Garvin�s and Hanssen�s¹² review of 29 studies examined the effect of antibiotic bone cement. Without antibiotic cement, a one-stage revision had a success rate of 58% compared to 82% with a two-stage procedure. With anti-biotic cement, the one-stage cure rate was 82% compared to 91% with a two-stage technique. From this review researchers believed that the effect of antibiotic cement was greater in the one-stage revisions, and of lesser benefit in the two-stage procedures.

The Vancouver group led by Duncan and Masri have developed the Prosthesis of Antibiotic Loaded Acrylic Cement (PROSTALAC) system for treatment of prosthetic hip infections.^13,14 They reported 96 of 116 patients had successful treatment of infected total hip replacements (83%) using the two-stage technique.

Prophylaxis for Joint Arthroplasty
Buchholz et al¹⁵ provided early evidence of the effectiveness of antibiotic bone cement for prophylaxis in total joint surgery. They reported an infection rate of 6% in 1154 total hip replacements performed without antibiotic cement, which was reduced to approximately 2% in 1655 hip replacements performed with Palacos cement containing gentamicin. In contrast, Lynch et al¹⁶ did not show a decrease in infection rates with antibiotic cement in a series of cemented Charnley total hip arthroplasties.

Josefsson et al^17,18 provided a randomized prospective trial comparing gentamicin-loaded bone cement to cement without antibiotics in 1688 hips showing a 0.4% infection rate with antibiotic cement but with systemic antibiotics and a 0.9% infection without antibiotic loaded cement but with systemic antibiotics at the 5-year follow-up. However, by 10 years� follow-up, no significant difference existed. Also, there was no difference in the rate of aseptic loosening between the two groups. Persson et al¹⁹ showed that antibiotic bone cement reduced the risk of revision surgeries in a review from the Swedish Joint Registry and recommended the use of antibiotic-loaded cement and systemic antibiotics for prophylaxis.

Chiu et al²⁰ found a significant decrease in the incidence of infection of total knee replacements when antibiotic cement was used without stratification in a randomized prospective trial. This group also found a decreased incidence of infected total knee replacements in patients with diabetes mellitus when antibiotic cement was used.²¹

Elution of Antibiotics from Antibiotic-Loaded Cement

The release of added antibiotics from bone cement is a complex process, but important variables are the type of antibiotic, the type of cement, and the mixing conditions. Antibiotic is released from the surface of the cement, and from cracks and voids in the cement. Del Real et al²² divided elution into three phases based on in vitro tests. Thirty percent of the antibiotic was eluted in the first 10 hours (phase 1). Sixty percent of the antibiotic was eluted in the next 16 days (phase 2), and the final 10% of the antibiotic was released in the next 54 days (phase 3). Although the majority of the antibiotic release will occur in the first 9 weeks, there was likely a low release of antibiotic through crack development. Evidence also exists that fracture of the cement mantle may liberate substantial levels of antibiotic years after the original procedure is performed.²³

The time course and amount of anti-biotic that is released from the cement is dependent on cement factors such as porosity and the surface area of the cement. Brien et al²⁴ assayed hemovac drainage after total hip arthroplasty and noted a much more consistent elution levels from tobramycin, with a variable elution from vancomycin added to the same cement types. Baker and Greenham²⁵ noted increased elution levels from Palacos cements over other cement types and attributed this to the increased porosity found in Palacos cements. This conclusion was challenged by Waertel.²⁶

Duncan and Masri²⁷ have measured tobramycin levels as high as 232 mg/L and vancomycin levels as high as 54 mg/L in the drainage fluid of patients after joint replacement, but systemic levels have not been measured above 3 mg/L (therapeutic serum levels are 7 mg/L for tobramycin, and 24 mg/L for vancomycin.). Tunney et al²⁸ reported that the minimum bacteriocidal concentration, which will kill 99.9% of the bacteria inoculum from their in vitro tests of bacteria recovered from revision surgeries, was >1024 mg/L for gentamicin in the gentamicin-resistant species. This suggests that some bacteria exist in which the minimum bacteriocidal concentration exceeds the maximum elution levels.

Adams et al²⁹ noted that some anti-biotics elute better than others out of the same cement type, which was Simplex P in their study, with clindamycin, vancomycin, and tobramycin displaying greater and more consistent elution profiles than cefazolin and ciprofloxacin.

Concerns about Antibiotic-Loaded Cement

Effect of Antibiotics on Structural Characteristics of PMMA
Numerous compounds have been developed to elute antibiotics over a period of time, but few provide the structural characteristics needed to anchor joint implants. There is evidence that the addition of antibiotic powder alters the mechanical properties, although, clinically, this has not caused an increase in the loosening rate in total hip replacement.¹⁹ Numerous studies have shown that the addition of 1 g of powdered antibiotic for 40 g of PMMA will not significantly affect the fatigue strength of the cement.^30-32 Bargar et al³³ showed that the addition of tobramycin (1.2 g per 40 g of PMMA) caused a 13% decrease in bending strength when compared to PMMA without antibiotics. Gogus et al³⁴ also saw a significant decrease in bending and compressive strengths. He et al³⁵ saw a slight drop in compressive strength in Palacos R with gentamicin over Palacos R without gentamicin.

The addition of >1 g of antibiotic powder per 40 g of PMMA (as is common in the fabrication of antibiotic beads and spacers) can cause significant weakening of the cement. Lautenschlager et al³⁶ demonstrated that adding more than 4.5 g of gentamicin powder per 40 g package of cement caused loss of compressive strength below American Society for Testing and Materials standards. This group also showed that the addition of liquid antibiotics caused a substantial loss in cement strength.³⁷

Numerous in vitro studies of PMMA without antibiotics have demonstrated the value of porosity reduction on the strength of the cement. Askew et al³⁸ found a 40% improvement in bending strength in vitro with the use of vacuum mixing and found that the effect was not changed with the addition of vancomycin or tobramycin.

Toxicity of Antibiotic Cement
Systemic toxicity related to the use of antibiotic-impregnated cement has not been reported. A common strategy in studies is to assess the antibiotic concentration in a patient�s blood after use of antibiotic-loaded cement to allow comparison to the vast amount of literature available on intravenous administration of antibiotics. Chohfi et al³⁹ studied vancomycin pharmacokinetics in 10 patients after total hip arthroplasty and found that blood levels of vancomycin were never >3 mg/mL, which was 30 times less than the toxic level of 90 mg/mL. Pritchett and Bortel⁴⁰ found similar low blood levels with the use of tobramycin in the antibiotic-loaded cement when 1.2 g of tobramycin were used per 40 g of PMMA. In a study of patients after total joint replacement, Duncan and Masri²⁷ found similar safe levels even with much higher doses of tobramycin. They recorded serum tobramycin levels of <3 mg/L despite use of up to 3.6 g of tobramycin powder per 40 g of bone cement. Animal studies have not shown any evidence of allergic reactions to antibiotic elution from bone cement.⁴¹

Local toxicity to cells at the interface of the antibiotic cement have not been reported, but few studies have examined changes in cell function. Pedersen and Lund⁴² examined the effect of gentamicin-loaded bone cement on mouse calvarial cultures and found that the addition of antibiotic to the cement caused decreased bone turnover presumably through decreased osteoblast and osteoclast function. Isefuku et al⁴³ noted that gentamicin levels of >100 mg/L inhibited osteoblast proliferation in in vitro experiments.

Antibiotic Resistance from Antibiotic Bone Cement
Enough experimental data exist suggesting the potential for development of bacterial antibiotic resistance that the use of antibiotic-impregnated cement should be performed only for clear indications. Kendall et al⁴⁴ noted survival of bacteria on antibiotic loaded cement in vitro. Hope et al⁴⁵ retrospectively reviewed 91 total hip replacements that were infected with coagulase-negative Staphylococcus and found that out of the patients who had had antibiotic cement in their reconstruction, 88% had development of resistant bacteria, whereas in patients who had not received antibiotic cement only 16% had resistant bacteria.

Tunney et al²⁸ cultured bacteria from prostheses retrieved at revision surgery (including many patients where no infection was suspected). They isolated 49 strains of bacteria from 26 of 120 prostheses exchanged at revision surgery. Of the 30 strains of Staphylococcus species isolated, 74% were resistant to gentamicin. In a study of 33 infected hip joints, Weber and Lautenbach⁴⁶ noted that 29% of bacteria isolated preoperatively were resistant to gentamicin.

Neut et al⁴⁷ assayed antibiotic-loaded cement beads removed at the time of the second stage of a two-stage procedure for infection in humans and noted that concentrated culture techniques revealed the presence of bacteria on these beads in 18 of 20 cases. Nineteen of the 28 bacterial strains isolated in this study were resistant to gentamicin. Thomes et al⁴⁸ inoculated rats with subcutaneous injections of gentamicin-sensitive S epidermidis adjacent to bone cement disks loaded with either saline or gentamicin. Although there was a lower rate of infection in the rats with gentamicin-loaded cement, a significantly higher level of gentamicin resistance was found. It also appears that certain bacteria can grow better on one type of biomaterial than another, with S epidermidis more capable of forming a biolayer on PMMA, and S aureus more capable of forming biofilms on metallic surface.⁴⁹ Wininger and Fass⁵⁰ reported that infection rates at Ohio State University Medical Center decreased with the use of antibiotic-loaded cement, but the prevalence of aminoglycoside-resistant bacteria had increased to 20% of S aureus species, and 60% for S epidermidis infections.

Controversy exists about the importance of bacterial and fungal attachment to the prosthesis by biofilms in the development of antibiotic resistance. Archiola et al⁵¹ showed a significant decrease in susceptibility of S epidermidis to beta lactam antibiotics and a lesser decrease in susceptibility to vancomycin after attachment.

Chandra et al⁵² found that the development of a biofilm by Candida albicans progressed through three phases, and development of resistance was seen only in the later phases. Conversely, Montanaro et al⁵³ studied Staphylococcus adhesion to PMMA and did not find any increase in the rate of resistance in the adherent and nonadherent bacteria.

Recommendations for Use of Antibiotic-Loaded Cement

Data show the advantages of antibiotic-loaded cement in one- and two-stage revisions of septic total joint arthroplasties, although the data are more compelling for one-stage exchanges. Preoperative aspiration is important because it affords a surgeon the chance of identifying the bacterial strain and its sensitivities so that the best antibiotic can be selected for the cement. In the first stage of a two-stage treatment for infected total hip replacement, the structural properties of the cement are not as important and larger doses and multiple types of antibiotic can be used (up to 3.6 g of powder per 40 g of cement has been described). In reconstructions in which the material properties of the cement are important, the aggregate in vivo and in vitro data support the use of up to 1 g of antibiotic powder per 40 g of cement.

The use of antibiotic-loaded cement for revision surgery of aseptic joints appears warranted due to clinical evidence of bacterial colonization of prostheses thought to be aseptically loose, as well as data from the Scandinavian joint registries of decreased cost when antibiotic-loaded cement was used in the revision surgery.^19,28,54

The use of antibiotic-loaded cement for prophylaxis in primary joint arthroplasty is controversial. Due to increasing evidence of the risk of development of antibiotic resistance, antibiotic-loaded cement should be used only for arthroplasties at high risk for development of infection. This would include patients with a history of previous infection of the involved joint, as well as patients with multiple previous surgeries on the joint, particularly those with failed internal fixation of periarticular fractures. It would also include patients with insulin-dependent diabetes mellitus. Patients with some degree of immune suppression may also be candidates for antibiotic-loaded cement, including patients with organ transplantation on immunosuppressive agents, steroid-dependent patients (asthma, inflammatory arthritis), patients with malnutrition (decreased albumin, decreased lymphocyte count), and patients >80 years of age.

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Author

From the Department of Orthopedic Surgery, Virginia Commonwealth University Health System, Richmond, Va.