Journal of the American Academy of Orthopaedic Surgeons 38 In 1970, Buchholz and Engelbrecht 1 introduced the concept of impreg- nating acrylic bone cement with antibiotic as a possible means of preventing infection in patients undergoing total joint arthroplasty. Since then, antibiotic-impregnated cement has become more commonly used for revision total joint arthro- plasty and, as antibiotic-impregnated cement spacers or beads, for treat- ment of infection during two-stage revision arthroplasty than it has for infection prophylaxis in primary total joint arthroplasty. Even with- out the contribution of antibiotic- impregnated cement, the infection rate after standard primary total joint arthroplasty in modern oper- ating rooms has been reduced to between 0.3% and 2%. A survey from 1995 concerning orthopaedic operating room practices and equip- ment suggested that this reduction has been achieved by the access to laminar airflow (present in 49% of hospital operating rooms), body exhaust suits (in 69%), high airflow (in 85%), and ultraviolet lights (in 14%). 2 Reported infection rates after revision total joint arthroplasty vary widely because of the large number of patient variables. Several types of acrylic bone cement in current use incorporate antibiotics, either premixed by the manufacturer or added by the sur- geon in the operating room. In the United States, commonly used cements such as Palacos (Smith & Nephew, Memphis, TN), Simplex (Howmedica, Rutherford, NJ), CMW (DePuy, Warsaw, IN), and Zimmer (Zimmer, Warsaw, IN) are mixed with antibiotics by the sur- geon. Commercially prepared ad- mixtures such as AKZ (Simplex P with colistin and erythromycin), Refobacin-Palacos R (Palacos R with gentamicin cement), and Septopal (beads of Palacos R with genta- micin) are not currently available in the United States. Some hospital pharmacies (2.2%) prepackage ce- ment with antibiotic for later use in the operating room. 3 A survey of 1,015 orthopaedic surgeons in the continental United States revealed that 56% have im- pregnated their bone cement with antibiotic for at least some cases. 2 Surgeons specializing in joint recon- struction were more likely to use antibiotic in bone cement (88%). Sixty-five percent of all surgeons surveyed reported that they adjust- ed antibiotic usage according to microbial sensitivity; of this group, 70% used tobramycin; 26%, genta- micin; 18%, vancomycin; 15%, cephalosporins; and 3%, combined antibiotics. Antibiotics in liquid Dr. Joseph is resident, Department of Ortho- paedic Surgery, Musculoskeletal Research Center, NYU–Hospital for Joint Diseases, New York, NY. Dr. Chen is resident, Department of Orthopaedic Surgery, Musculoskeletal Research Center, NYU–Hospital for Joint Diseases, New York. Dr. Di Cesare is Associate Professor of Orthopaedic Surgery, Department of Ortho- paedic Surgery, Musculoskeletal Research Center, NYU–Hospital for Joint Diseases, New York. Reprint requests: Dr. Di Cesare, 15th Floor, 301 East 17th Street, New York, NY 10003. Copyright 2003 by the American Academy of Orthopaedic Surgeons. Abstract The use of antibiotic-impregnated cement in revision of total hip arthroplasty pro- cedures is widespread, and a substantial body of evidence demonstrates its effi- cacy in infection prevention and treatment. However, it is not clear that it is necessary or desirable as a routine means of prophylaxis in primary total joint arthroplasty. In the management of infected implant sites, antibiotic- impregnated cement used in one-stage exchange arthroplasties has lowered rein- fection rates. In two-stage procedures, use of beads and either articulating or nonarticulating antibiotic-impregnated cement spacers also has lowered reinfec- tion rates. In addition, spacers reduce “dead space,” help stabilize the limb, and facilitate reimplantation. Problems associated with antibiotic-impregnated cement in total joint arthroplasty include weakening of the cement and the genera- tion of antibiotic-resistant bacteria in infected implant sites. J Am Acad Orthop Surg 2003;11:38-47 Use of Antibiotic-Impregnated Cement in Total Joint Arthroplasty Thomas N. Joseph, MD, Andrew L. Chen, MD, and Paul E. Di Cesare, MD Thomas N. Joseph, MD, et al Vol 11, No 1, January/February 2003 39 form, generally considered to be less desirable than the powdered form (because of the effects to cement polymerization), were used by as many as 11% of the surgeons surveyed, possibly because of the general unavailability of a pow- dered form of gentamicin in the United States. In performing prima- ry arthroplasties, approximately 12% of surgeons always used anti- biotic-impregnated cement, 69% never used it, and 19% used it some- times. Of those who did use it, 68% did so in less than one third of their aseptic revision total joint arthro- plasties. However, over 80% used it more than two thirds of the time in septic revision total joint arthroplas- ty. Over half often used antibiotic- impregnated cement beads in two- stage reimplantation for infections; 32% often used antibiotic-impreg- nated cement spacers in hips; and 69% often used such spacers in knees. Of those using antibiotic- impregnated cement, 28% used a single-stage reimplantation in total joint arthroplasty infection, while 72% used a two-stage approach. 2 These data suggest that no com- monly accepted standard exists regarding the use of antibiotic- impregnated cement in orthopaedic surgery. The FDA takes no official posi- tion on the use of antibiotics in cement. A document issued July 17, 2002, requires that cement labeling contain the warning, “PMMA bone cement is contraindicated in the presence of active or incompletely treated infection, at the site where the bone cement is to be applied.” 4 Laboratory Studies A number of criteria must be met for antibiotics to be effective when mixed with methylmethacrylate. The preparation must be sufficiently thermally stable to withstand the heat of polymerization. The antibi- otic must not be adversely affected by body temperature and must be water soluble so that it can diffuse into surrounding tissues. The antibiotic must have a bactericidal effect at the tissue levels attained; furthermore, it must be released gradually over an appropriate time period. The preparation must evoke minimal local inflammatory or allergic reaction. Development of resistance should be rare to nonexis- tent; common pathogens must be considered, including Staphylococcus aureus, S epidermidis, coliform, and others, such as anaerobes. Finally, the antibiotic must not significantly compromise mechanical integrity, especially if the cement is used for implant fixation. In vitro analyses of antibiotic elu- tion and mechanical stability have been done with a variety of antibiot- ic-cement combinations. The stable incorporation of aminoglycoside antibiotics (eg, gentamicin and tobramycin) into cement and their elution therefrom are well estab- lished. Vancomycin is gaining pop- ularity because of its effectiveness against methicillin-resistant bacteria as well as its general availability. Although penicillins and cephalo- sporins exhibit adequate elution and stability, they are often avoided be- cause of their potential allergenicity. In one study, in vitro testing of van- comycin- and tobramycin-impreg- nated cement demonstrated elution of antibiotic for the entire 9-week study period; the highest elution rate occurred at 18 hours (between 3 and 5 times the rate that occurred at 72 hours). 5 Ciprofloxacin, a more re- cent addition to bone cement, may gain in popularity because of its wide antibiotic spectrum and gener- al availability. Ciprofloxacin elution met or exceeded the minimum inhibitory concentration for com- mon organisms associated with osteomyelitis for up to 42 days. 6 Recent studies 7,8 indicate that ciprofloxacin may inhibit bone, liga- ment, and soft-tissue healing; this is a concern, particularly in total knee revision surgery. Lipids may impede the leaching process from cement. The peptide antibiotics vancomycin and poly- myxin B nonapeptide have been shown to elute for a longer period than do the nonpeptide antibiotics gentamicin, novobiocin, and eryth- romycin. 9 Molecular weight also appears to play a role. One in vitro study indicated that vancomycin is eluted 10 times less efficiently than tobramycin from antibiotic-impreg- nated cement, probably because of its higher molecular weight. 10 Other in vitro studies, however, found no marked difference between the two. 11 Palacos cement appears to pro- vide the best elution profile for most antibiotics. A study of the elution characteristics of Palacos and CMW acrylic cements showed that CMW 1 released 24% less tobramycin and 36% less vancomycin than did Pala- cos; CMW 3 released 34% less tobra- mycin and 38% less vancomycin. 5 Another in vitro study, in which Palacos and Simplex beads and spacers were impregnated with 4 g of either vancomycin or tobramycin in 40 g of cement, also showed antibiotic eluting from Palacos at higher levels. 12 Concentrations re- mained above the minimum inhibi- tory concentration for S aureus longer in Palacos than in Simplex. In another study, elution of van- comycin, daptomycin, and amikacin from Palacos exceeded that of Simplex, Zimmer Dough-Type, and Zimmer LVC. 13 Commercially prepared antibiot- ic cement may be superior to intra- operatively mixed cement. Elution of gentamicin and tobramycin from laboratory-customized Zimmer, Simplex, or Palacos beads compared with elution from commercially pre- pared gentamicin-PMMA (Septopal) beads showed that more total an- tibiotic was eluted from the latter, and was maintained at higher con- Antibiotic-Impregnated Cement in Total Joint Arthroplasty Journal of the American Academy of Orthopaedic Surgeons 40 centrations, than it was in the beads to which antibiotics were added by the investigators. 14 The results of studies of the effect on elution of combinations of antibi- otics, typically vancomycin and tobramycin, are inconclusive. In one study, elution of vancomycin was minimally affected by tobramycin, while elution of tobramycin was reduced by vancomycin. 10 In anoth- er study, the elution rate of tobramy- cin increased by 68% and that of van- comycin by 103% when these antibi- otics were combined. 15 In the first study, 10 vacuum-mixed Simplex was used, and in the second, 15 nonvacu- um-mixed Palacos. In both, the most advanced means of measuring an- tibiotic were used. An in vivo study using the prosthesis of antibiotic- loaded acrylic cement (PROSTA- LAC; Smith & Nephew, Memphis, TN) demonstrated a statistically sig- nificant (P = 0.011) increase in the elution of vancomycin when the dose of tobramycin was increased from 2.4 to 3.6 g per dose of cement; Simplex was used in 12 patients and Palacos in 37. 16 The investigators changed the cement early in their study after finding evidence in the literature suggesting better antibiotic elution from Palacos. Klekamp et al 10 demonstrated that compressive and fatigue strength decreased with the addition of van- comycin or tobramycin to cement. Cement impregnated with 1, 2, or 3 g of vancomycin failed at 90%, 70%, and 50%, respectively, of the num- ber of cycles to failure for antibiotic- free cement. Likewise, cement with 1.2 and 2.4 g of tobramycin failed at 80% and 60%, respectively, of the number of cycles to failure for con- trols. Although fatigue strength data were statistically significant (P < 0.05), the results of compressive strength tests demonstrated a de- creasing trend yet were not statisti- cally significant. Routinely used lyophilized vancomycin was found to greatly reduce cement fatigue strength. The authors suggested using vancomycin P (an ultrafine powder) in bone cement intended for prosthesis fixation because it has less detrimental effect on cement strength. Askew et al 17 found that the addition of 1 g of either tobra- mycin or vancomycin resulted in nominal bending strength reduc- tions (6% and 1%, respectively, compared with controls). Another study confirmed that the addition of 1.2 g of tobramycin to 40 g of Sim- plex powder did not significantly de- crease fatigue strength. 18 Vancomy- cin L (lyophilized) should be finely ground when used for prosthesis fixation to prevent mechanical weakening; however, large crystals should not be completely pulver- ized when preparing beads or spac- ers because the crystals facilitate antibiotic elution. Morita and Aritomi 19 showed no reduction in tension and bending strengths of cefuzonam-impregnated cement when <3 g was used. Earlier studies showed similar results with respect to compressive and tension strengths of cement impregnated with gentamicin, oxacillin, and cefa- zolin. 20 Addition of more than 4.5 g of gentamicin has been shown to substantially weaken cement to a level below that appropriate for implant fixation. 21 Reduction of no more than 10% in bone cement strength is considered acceptable for use in total joint arthroplasty fixa- tion; however, weaker antibiotic- impregnated cement may be used in beads and spacers. Table 1 lists ap- propriate doses of antibiotic im- pregnation in cement for prosthesis fixation and for spacers and beads. Vacuum mixing, which reduces the number of voids in bone ce- ment, improves the mechanical properties of antibiotic-impregnated cement. When cylindrical cement- vancomycin specimens were sub- jected to fatigue testing (uniaxial mode), cycles to failure were 15% to 58% greater in vacuum-mixed speci- mens than in those mixed at atmos- pheric pressure. Fracture of antibi- otic-impregnated cement specimens during cyclic testing was reduced up to tenfold with vacuum mixing or with vigorous pulverizing of the antibiotic before mixing. 10 Another study showed vacuum mixing also reduced fivefold the radiograph- ically apparent porosity of antibiotic- impregnated cement specimens but may inhibit antibiotic release. 17 In Table 1 Reported Doses * of Antibiotics Used in Antibiotic-Impregnated Cement 13,26,44,53-55 Antibiotic Dose for Prosthesis Fixation Dose for Spacers and Beads Amikacin 1 g 2 g Cefazolin NR 4 to 8 g Cefotaxime 3 g NR Cefuroxime 1.5 to 3 g NR Clindamycin NR 4 to 8 g Erythromycin 0.5 to 1 g NR Gentamicin 1 g 2 to 5 g Ticarcillin Not appropriate 5 to 13 g Tobramycin 1.2 g 2.4 to 9.6 g Vancomycin 1 g (vancomycin P) 3 to 9 g (vancomycin P or L) * Per 40-g batch of cement P = ultrafine powder, L = lyophilized, NR = not reported in the literature Thomas N. Joseph, MD, et al Vol 11, No 1, January/February 2003 41 one study, vancomycin vacuum- mixed with Simplex (1:40 ratio) released slightly less than half the antibiotic that air-mixed cement did; no antibiotic release was detectable after 48 hours. 13 Another study, however, found adequate antibacte- rial activity lasting for 21 days. 17 Dextran has been used to en- hance porosity and thus improve the elution of antibiotic. One prepara- tion with dextran released approxi- mately 4 times as much antibiotic as did a dextran-free preparation, and elution remained detectable for 10 days versus 7 days, respectively. 13 However, dextran degrades the mechanical properties of cement; therefore, its use for prosthetic fixa- tion should be extremely limited. Centrifugation, another preparation technique, markedly increased the fatigue life of Simplex both with and without tobramycin by a factor of eight. Increase in the surface area of antibiotic-impregnated cement spac- ers has been shown to increase elu- tion of antibiotic in vitro. Holtom et al 22 demonstrated that fenestrated spacers with a 40% greater surface area resulted in a 20% higher elution rate of vancomycin from Palacos ce- ment than from standard or donut- shaped spacers. Masri et al 23 demon- strated a significant (P = 0.05) in- crease in the elution of tobramycin over 1 week with the use of Simplex- impregnated blocks that had a 9% increased surface area-to-volume ratio. Antibiotics in liquid form mixed with cement dilute the catalyst that is needed for the cement curing process, thereby adversely affecting both the curing time and final mechanical properties of cement; accordingly, they are not recom- mended. Table 2 lists antibiotics that can be mixed with cement. In Vivo Studies The penetration of antibiotics re- leased from antibiotic-impregnated cement into surrounding tissues has been evaluated in both animal and human studies. Concentrations of antibiotic in hematoma, granulation tissue, and bone vary according to antibiotic. Local concentrations, however, have been found to be consistently higher than serum con- centrations and usually exceed the minimum inhibitory concentrations for target pathogens. The elution of several antibiotics from Simplex cement was measured in samples from dogs over a 28-day period. 24 Clindamycin, vancomy- cin, and tobramycin exhibited elu- tion characteristics that reached con- sistently high levels in bone and granulation tissue. Cefazolin and ciprofloxacin were maintained at high concentrations in granulation tissue but at low levels in seroma and bone. Ticarcillin showed unfa- vorable elution characteristics in granulation tissue, seroma, and bone. Experimentally produced para- spinal wounds (fractured, infected spinous processes) in rabbits were treated with either a chain of to- bramycin antibiotic-impregnated cement beads, beads without antibi- otics, systemic antibiotics only, or nothing. 25 At 5 days, no recoverable organisms were found in six of eight animals treated with antibiotic- impregnated cement beads. Six of eight rabbits receiving systemic tobramycin had wound infections. All five animals in which nonantibi- otic-impregnated cement beads were implanted had significant infections; one died from sepsis. All four ani- mals that received no treatment were infected. Antibiotic concentrations were measured in wound drainage fluid, urine, and serum from 50 patients who underwent primary total hip arthroplasty (THA) and received tobramycin or vancomycin deliv- ered either in antibiotic-impregnated cement or by intravenous adminis- tration (not both). 26 No significant differences were found between Table 2 Antibiotics Used in Antibiotic-Impregnated Cement Decreased Activity Because Adversely Affected Can Be Mixed With Cement of Cement Heat by Cement Curing Amikacin Cefuzonam Erythromycin Penicillin Chloramphenicol Liquid gentamicin, Amoxicillin Cephalothin Gentamicin Polymyxin B Colistimethate clindamycin, etc (because Ampicillin Ciprofloxacin (powder) Streptomycin Tetracycline of aqueous content) Bacitracin Clindamycin Lincomycin Ticarcillin Rifampin Cefamandole (powder) Methicillin Tobramycin Cefazolin Colistin Novobiocin Vancomycin Cefuroxime Daptomycin Oxacillin Antibiotic-Impregnated Cement in Total Joint Arthroplasty Journal of the American Academy of Orthopaedic Surgeons 42 Simplex and Palacos surgeon- prepared antibiotic-impregnated cement. Serum and urine antibiotic levels were significantly (P ≤ 0.05) higher in the intravenous group than in the impregnated-cement group. Wound drainage fluid levels of tobramycin were significantly (P ≤ 0.05) higher in the antibiotic- impregnated cement group than in the intravenous group, whereas the vancomycin intravenous group had higher antibiotic levels in wound drainage fluid than did the van- comycin cement group. In the cement group, tobramycin exhibited a consistently high level of bioactivity against S epidermidis in wound drainage fluid, while vancomycin lost all bioactivity by 24 hours. In 30% of cases, no vancomycin was detected in the wound drainage fluid of the cement group. Overall, tobramycin exhibited adequate local tissue levels and released antibiotic effectively, whereas vancomycin exhibited inadequate elution prop- erties. Clinical Studies Primary Total Joint Arthroplasty Because of the low rates of infec- tion experienced with total joint arthroplasty procedures, researchers seeking to demonstrate statistically significant differences with the pro- phylactic use of antibiotic-impreg- nated cement require a very large sample size with multicenter partici- pation. A prospective, randomized study in Sweden combined results from nine orthopaedics departments (1,688 consecutive THAs) to com- pare the prophylactic effect of systemic antibiotics to that of genta- micin-impregnated cement alone. At a mean follow-up of 10 years, the infection rate was 1.6% in the sys- temic antibiotic group and 1.1% in the gentamicin-impregnated cement group, a difference that was not sta- tistically significant. 11 No cases of nephrotoxicity, ototoxicity, or aller- gic reaction were reported. More than 10,000 primary ce- mented total hip replacements done for osteoarthritis and reported to the Norwegian arthroplasty registry were studied retrospectively. 27 Four groups were compared: patients receiving antibiotic prophylaxis both systemically and locally in antibiotic- impregnated cement, those receiv- ing antibiotics only systemically, those receiving only antibiotic- impregnated cement, and those receiving no antibiotic prophylaxis. The antibiotic-impregnated cement was either Palacos with gentamicin or AKZ (erythromycin and colistin with Simplex). The rate of revision done for any reason was 2.0% (94/4,586) in patients receiving only systemic antibiotics, 4.2% (10/239) for antibiotic-impregnated cement only, 1.2% (70/5,804) for the com- bined regimen, and 2.5% (7/276) for no antibiotics. Among cases that sub- sequently required revision for in- fection, the lowest revision rate, 0.14% (8/5,804), was in patients who received both antibiotic-impregnated cement and systemic antibiotics. A prospective, randomized clini- cal trial of 401 patients in two British centers compared the effect of cefuroxime-impregnated cement and cefuroxime administered sys- temically on infection after total joint arthroplasty. 28 No statistically significant difference was found between the two groups with respect to incidence of superficial wound infection or early deep infec- tion (1% in both groups). There were no late deep infections after 2- year follow-up. Hope et al 29 found at least one strain of gentamicin-resistant coag- ulase-negative staphylococcus in 30 of 34 cases of deep infection (88%) in which cement containing gentamicin had been used. In contrast, only 9 of 57 patients (16%) in whom antibi- otic-free cement was used exhibited gentamicin-resistant coagulase-neg- ative staphylococcus. Revision Arthroplasty Revision arthroplasty usually is accompanied by rates of infection significantly higher than rates for primary arthroplasty. Revision arthroplasties done for infection are either one- or two-stage procedures. Two-stage revisions are more com- mon, but they can be technically demanding because of scar forma- tion, limb shortening, disuse osteo- porosis, and altered anatomy. Although advocates of two-stage reimplantation cite infection rates lower than those of one-stage revi- sions, carefully selected patients can be treated with comparable success with one-stage revisions using antibiotic-impregnated cement. In one review of the literature, success rates of one-stage exchange with and without the use of antibiotic-impreg- nated cement were 81% and 71%, respectively; the success rates of two-stage reimplantation with and without antibiotic-impregnated cement were 93% and 82%. 30 One-Stage Revision for Infection One-stage exchange arthroplasty using antibiotic-impregnated ce- ment has been advocated in defined instances for the treatment of an infected total joint arthroplasty. In a multicenter comparison of one- and two-stage exchange arthroplasties for infection conducted in the 1970s, a success rate of approximately 80% was found for both methods. 31 Gentamicin-loaded Palacos and 6 months of systemic antibiotics were used in all procedures. The results were slightly better for one-stage exchanges; however, follow-up was relatively short (0.5 to 3.5 years). In a study of 235 one-stage exchanges for THA infection using antibiotic- impregnated cement, 11% with per- sistent infection failed; another 3% of cases with suspected infection failed. 32 Of the 61 two-stage ex- changes, which used antibiotic- Thomas N. Joseph, MD, et al Vol 11, No 1, January/February 2003 43 impregnated cement beads for peri- ods of from 6 weeks to 9 months, 5% failed from reinfection. Hope et al 29 reviewed a series of 91 patients with deep infection of a cemented THA caused by coagulase-negative staphylococcus. In this series, 72 pa- tients were treated with one-stage exchange arthroplasty; 9 (13%) failed because of recurrence of infec- tion. Gentamicin was used in com- bination with other antibiotics based on organism sensitivities. The other 19 patients underwent a two-stage exchange without any failures. Although it has been suggested that a contraindication to one-stage reimplantation is infection with a gram-negative organism, a study of 15 patients with gram-negative infection treated with one-stage THA revision found only 1 recur- rence (6.7%) at a mean follow-up of 8 years. Palacos cement with gen- tamicin was used in 13 of 15 pa- tients, with other antibiotics added to cement as appropriate. 33 In a larger study of 183 patients with similar follow-up (mean, 7.75 years), one-stage revision with both antibi- otic-impregnated cement and sys- temic antibiotics was used for deep infection of a THA. 34 Twenty-nine of these patients (16%) had evidence of persistent infection and 154 (84%) were free of infection on follow-up. None of the 29 patients who experi- enced failure was infected with gram-negative organisms. For patients undergoing revision arthroplasty, Garvin et al 35 devel- oped a classification system of high-risk, suspicious, and definite infection categories. These were based on Gram stains, cultures, intraoperative findings, clinical diag- noses, radiographic findings, and laboratory results. 35 In a prospec- tive clinical study, gentamicin- impregnated Palacos was used for prosthesis fixation in 67 high-risk, 32 suspicious, and 31 definite infec- tions. All but one of the high-risk patients underwent one-stage pro- cedures; those with suspicious or definite infections underwent either one- or two-stage procedures plus 6 weeks of intravenous antibiotics. Postoperative infection occurred in 5 of the 92 one-stage patients (5.4%) and in none of the 38 two-stage patients. Of the 67 high-risk patients, 3 (4.5%) developed post- operative infections; one was then revised with a successful two-stage procedure. Of the 32 patients suspi- cious for infection, 19 underwent one-stage implantation; one of them developed a postoperative infection. The other 13 patients with suspi- cious infection underwent success- ful two-stage implantation. Of patients with definite infection, 7 of 31 underwent one-stage implanta- tion, with one of them developing a postoperative infection; 24 patients had a successful two-stage implan- tation. To test that one-stage revisions can be successful if rigid criteria are met, Ure et al 36 prospectively fol- lowed 20 consecutive patients under- going one-stage THA for infection between 1979 and 1990. Surgical management included meticulous débridement, use of antibiotic- impregnated cement, and systemic antibiotic therapy. Patients were excluded from this treatment when they were immunocompromised, had an infection with a known resis- tant gram-negative or methicillin- resistant organism, or had a major skin, soft-tissue, or osseous defect. At a mean follow-up of 9.9 years, no patient had experienced recurrence of infection. Two patients required revision for aseptic loosening. Parenteral antibiotics were adminis- tered postoperatively for a mean of 4.7 months. Two-Stage Revision for Infection By reducing dead space, cement spacers help stabilize the limb awaiting reimplantation (Fig. 1). Complications include bone loss, dislocation, continued pain, de- creased mobility, and (rarely) frac- ture. Local antibiotic delivery with cement spacers, cement beads, or a PROSTALAC has been used after component removal in a two-stage procedure. Additionally, antibiotic- impregnated cement can be used for prosthesis fixation during reimplan- tation in the second stage. Antibiotic-impregnated cement spacers used in the first stage of two-stage reimplantation can deliv- er a high concentration of antibiotics to the infected area. In a retrospec- tive study, Calton et al 37 treated 25 infected total knee prostheses in 24 patients with débridement, compo- nent removal, and insertion of an antibiotic-impregnated cement block. Intravenous antibiotics were admin- istered for 6 weeks; patients’ knees were kept immobilized with no weight bearing. The success rate was 92% (2 failures) at a mean fol- low-up of 36 months; 15 of 25 knees exhibited either tibial or femoral bone loss caused by invagination of the cement spacer block into the cancellous bone. Leunig et al 38 re- ported on 12 patients with deep infections of hip implants who un- derwent two-stage revision and were treated using gentamicin- loaded cement. Spacers were used for a mean of 4 months; during that period, six spacers failed, five by dislocation and one by fracture. At a mean follow-up of 27 months after reimplantation arthroplasty, all patients were mobile and infection free. An articulating spacer used in two-stage revision for infected total knee arthroplasty may improve patient mobility and allow partial weight bearing. This would pro- mote healthier soft tissues, improve wound healing, allow easier reim- plantation, improve bone quality and range of motion, and reduce complications. Hofmann et al 39 treated 26 patients who had late- infected total knee arthroplasties with two-stage revision using an articulating spacer with tobramycin- Antibiotic-Impregnated Cement in Total Joint Arthroplasty Journal of the American Academy of Orthopaedic Surgeons 44 impregnated cement. The spacer was prepared by cleaning, autoclav- ing, and reinserting the femoral component. A new tibial polyethyl- ene insert and in some cases a new all-polyethylene patellar component were used to place a large amount of antibiotic-impregnated cement between each insert and bone. Patients were treated with 6 weeks of intravenous antibiotic therapy. Reimplantation was performed 6 to 12 weeks after placement of the spacer. All but one patient (who died of systemic complications) underwent successful reimplanta- tion (96%). At a mean follow-up of 31 months, knee scores had improved and no recurrence of in- fection was found. Complications of early articulat- ing spacers included tibiofemoral instability and patellar instability; results subsequently have improved with design modifications. A recent study by Fehring et al 40 failed to show any difference in range of motion or knee scores between articulating and static antibiotic- impregnated cement spacers used in two-stage revisions. The ar- ticulating spacers were custom-pre- pared using a stainless steel femoral component mold and stemmed tibial baseplate of antibiotic-impregnated cement. Nevertheless, reimplanta- tion was facilitated, and less bone loss occurred with articulating spac- ers than with static antibiotic- impregnated spacers. Lai et al 41 reported on 40 infect- ed hip prostheses treated with component removal, intravenous and oral antibiotics for 8 weeks, and delayed reimplantation (mean, 48 weeks) with cementless compo- nents. At mean of 4 years’ follow- up, 5 patients (13%) had experi- enced recurrent infection: 2 of 33 from the group treated with Sep- topal (gentamicin) beads, and 3 of 6 of those treated without antibiotic- impregnated cement beads. A pro- spective, randomized, multicenter study of 6 infected total knee and 22 infected hip arthroplasties in 28 patients compared two-stage re- implantation using gentamicin- impregnated cement beads with that using conventional parenteral systemic antibiotic therapy for 6 weeks postoperatively. 42 At a mean follow-up of 3 years, infection recurred in 2 of 15 patients treated with gentamicin-impregnated cement beads (13%) and in 4 of 13 patients treated with conventional systemic antibiotic therapy (31%); however, this was not statistically significant. Whiteside 43 used allo- graft technique with cementless revision arthroplasty for massive tibial and femoral defects in 33 chronically infected total knee arthroplasties. Treatment included implant removal, débridement, and rigidly fixed antibiotic-soaked bone graft followed by 6 weeks of antibi- otic-impregnated cement beads and intravenous antibiotics. The success rate of the two-stage procedure was 85%. Infection recurred in five knees; however, repeated procedures al- lowed successful revision in all but one, which required an above-the- knee amputation. Although use of antibiotic-impregnated cement beads or spacers is common in two-stage revisions, one study showed that their use in two-stage revisions was not correlated with cure rate for infection. 44 The PROSTALAC, introduced in 1989, is a temporary hip prosthesis composed of a thin polyethylene acetabular cup and a stainless steel femoral component, both of which are loosely cemented with antibiotic- impregnated cement (Fig. 2). Bene- fits include early mobilization, accel- erated rehabilitation, and early hos- pital discharge. The device maintains soft-tissue planes and leg lengths and has made second-stage proce- dures easier to perform. Younger et al 45 reviewed 48 patients who had Figure 1 Anteroposterior (A) and lateral (B) radiographs of an antibiotic-impregnated cement spacer in a two-stage revision total knee arthroplasty. A B Thomas N. Joseph, MD, et al Vol 11, No 1, January/February 2003 45 undergone two-stage arthroplasty of an infected hip replacement using the PROSTALAC. All but three pa- tients were free from persistent infection, for an eradication rate of 94%. More recently, Younger et al 46 evaluated PROSTALACs with a cement-on-cement articulation and with a custom metal-on-polyethyl- ene articulation. Of 28 infected total hips followed for a minimum of 2 years, 96% exhibited no evidence of infection. In a retrospective study of 89 re- vision procedures for infected total knee arthroplasties, persistent infec- tion occurred in 10 knees (11.2%). 44 No standardized protocol was used for treatment. In 64 knees, antibiotic- impregnated cement was used for implant fixation; in 25, no antibiotic- impregnated cement was used. Antibiotic-impregnated beads were used in 20 patients, antibiotic- impregnated spacers in 23, both used in 4, and neither used in 42 patients. When use of antibiotic- impregnated cement for implant fix- ation was factored in, the results were statistically significant. Of the 25 knees without antibiotic-impreg- nated cement, 7 (28%) developed recurrent infection, compared with only 3 (5%) of the 64 knees treated with antibiotic-impregnated cement (P < 0.01). Although antibiotic- impregnated cement beads or spac- ers appeared to be beneficial, their use was not statistically significant. We are not aware of any prospec- tive randomized study comparing antibiotic-impregnated cement beads or spacers to antibiotic- impregnated cement in prosthetic fixation. Antibiotics in Revision Arthroplasty Without Infection Although the use of antibiotic- impregnated cement in revision arthroplasty without evidence of infection has been advocated, the literature on the subject is scant and equivocal. Lynch et al 47 reported notably better results with genta- micin-containing cement for aseptic revisions than with cement alone (systemic antibiotics not used), a reduction from 3.5% to 0.8%. A ret- rospective analysis with minimum 2-year follow-up reported that in aseptic revision THAs or conversion from upper femoral prosthesis (pro- phylactic systemic antibiotics not used), infection rates were 0.5% for gentamicin-impregnated cement and 2.8% for cement alone. 47 The authors concluded that low-viru- lence organisms that are difficult to culture may be present in some cases thought to be aseptic loosen- ing and that the local antibacterial effect is responsible for the effective prevention and treatment of infec- tion in these patients. Experimental Cement-Antibiotic Combinations Ceramic composites have been considered for use as a vehicle for antibiotic delivery. In one laboratory study of a novel bioactive bone ce- ment (15% bisphenol-α-glycidyl methacrylate, 15% triethylene-glycol dimethacrylate resin, and 70% apatite- and wollastonite-containing glass-ceramic powder) containing cephalexin in the form of pellets, antibiotic release was initially rapid, slowed markedly after 24 hours, and was released continuously thereafter for 2 weeks. 48 The strength of the cement with cephalexin was approxi- mately twice that of acrylic antibiotic- impregnated cement. The authors suggested that this material may be suitable for prosthetic fixation as well as in beads or spacers. Another study tested the efficacy of a calcium hydroxyapatite ceramic with gen- tamicin in the form of blocks im- planted adjacent to stainless steel tibial inserts in rats that had been in- jected with S aureus. 49 Suppression of infection in the ceramic-genta- micin–treated animals was superior to that in controls, including those in which acrylic antibiotic-impregnat- ed cement was used. Biodegradable antibiotic-impreg- nated material offers a potential means of local antibiotic delivery for infection control or treatment with- out obligation for later removal. A biodegradable cement (composed of tricalcium phosphate and calcium carbonate with a matrix phase of polypropylene fumarate cross- linked with methylmethacrylate monomer) containing gentamicin and vancomycin was evaluated for treatment and prophylaxis of S aureus osteomyelitis in rat proximal tibias. 50 The treatment group exhib- ited significantly (P < 0.01) fewer colony-forming units than did con- trols. Sites treated prophylactically developed no infections. No signifi- cant difference was found between biodegradable cement and PMMA used as a carrier for antibiotics. Another study showed that the ten- sile strength of the material and the biologic activity of the antibiotic were maintained when gentamicin was added to a resorbable calcium phosphate cement composed of β-tricalcium phosphate, monocal- Figure 2 Anteroposterior radiograph of the PROSTALAC in a two-stage revision THA. Antibiotic-Impregnated Cement in Total Joint Arthroplasty Journal of the American Academy of Orthopaedic Surgeons 46 cium phosphate monohydrate, and water. 51 More recently, calcium hydrox- ide has been added to PMMA beads containing tobramycin. 52 The beads released hydroxyl and calcium ions into the culture medium as well as a greater amount of antibiotic than did beads containing only tobramy- cin. Bacterial growth was more effectively inhibited when S aureus was incubated with tobramycin- and calcium hydroxide–impregnat- ed PMMA disks than with disks containing only tobramycin. The study did not, however, address the effects of the tobramycin and calci- um hydroxide combination on the strength of the cement. Future uses may include fracture healing and bone grafting in addition to osteo- myelitis treatment and implant attachment. Summary Since its introduction in 1970, antibi- otic-impregnated cement has been used in total joint arthroplasty in a variety of situations. In both one- and two-stage revision procedures for infection, antibiotic-impregnated cement clearly reduces the reinfec- tion rate. The antibiotic should be chosen based on the infecting organism or, if preoperative cul- tures are unavailable, by assessment of likely pathogens. In two-stage procedures, the use of articulating spacers implanted with antibiotic- impregnated cement may improve reimplantation results as well as quality of life in the period between procedures. There is some sugges- tive evidence that if cement is to be used in apparently aseptic revision surgery cases, the cement should be antibiotic-impregnated because of the possibility that these culture- negative cases are indeed contami- nated. Because of the low rate of infections with established periop- erative and intraoperative protocols and the risk that using antibiotics will lead to the development of antibiotic-resistant bacteria, the rou- tine use of antibiotic-impregnated cement appears to be unnecessary in primary total joint replacement surgery. The future of antibiotic- impregnated cements may include stronger composites with more sus- tained release of a wide array of an- tibiotics. Bioabsorbable antibiotic- impregnated cements may further reduce reinfection rates in one-stage procedures by supplying additional local delivery of antibiotic via mate- rials that do not require later re- moval. References 1. Buchholz HW, Engelbrecht H: Depot effects of various antibiotics mixed with Palacos resins [German]. Chirurg 1970;11:511-515. 2. Heck D, Rosenberg A, Schink-Ascani M, Garbus S, Kiewitt T: Use of antibi- otic-impregnated cement during hip and knee arthroplasty in the United States. J Arthroplasty 1995;10:470-475. 3. Fish DN, Hoffman HM, Danziger LH: Antibiotic-impregnated cement use in US hospitals. Am J Hosp Pharm 1992; 10:2469-2474. 4. Class II special controls guidance docu- ment: Polymethylmethacrylate (PMMA) bone cement; guidance for industry and FDA. http://www.fda.gov/cdrh/ ode/guidance/668.html. Accessed December 16, 2002. 5. Penner MJ, Duncan CP, Masri BA: The in vitro elution characteristics of antibiotic-loaded CMW and Palacos-R bone cements. J Arthroplasty 1999;14: 209-214. 6. DiMaio FR, O’Halloran JJ, Quale JM: In vitro elution of ciprofloxacin from polymethylmethacrylate cement beads. J Orthop Res 1994;12:79-82. 7. Huddleston PM, Steckelberg JM, Hanssen AD, Rouse MS, Bolander ME, Patel R: Ciprofloxacin inhibition of experimental fracture healing. J Bone Joint Surg Am 2000;82:161-173. 8. Williams RJ III, Attia E, Wickiewicz TL, Hannafin JA: The effect of ciprofloxa- cin on tendon, paratendon, and capsu- lar fibroblast metabolism. Am J Sports Med 2001;28:262-263. 9. Yaniv M, Dabbi D, Amir H, et al: Pro- longed leaching time of peptide antibi- otics from acrylic bone cement. Clin Orthop 1999;363:232-239. 10. Klekamp J, Dawson JM, Haas DW, DeBoer D, Christie M: The use of van- comycin and tobramycin in acrylic bone cement: Biomechanical effects and elution kinetics for use in joint arthro- plasty. J Arthroplasty 1999;14:339-346. 11. Josefsson G, Kolmert L: Prophylaxis with systematic antibiotics versus gen- tamicin bone cement in total hip arthro- plasty: A ten-year survey of 1,688 hips. Clin Orthop 1993;292:210-214. 12. Greene N, Holtom PD, Warren CA, et al: In vitro elution of tobramycin and vancomycin polymethylmethacrylate beads and spacers from Simplex and Palacos. Am J Orthop 1998;27:201-205. 13. Kuechle DK, Landon GC, Musher DM, Noble PC: Elution of vancomycin, dap- tomycin, and amikacin from acrylic bone cement. Clin Orthop 1991;264:302-308. 14. Nelson CL, Griffin FM, Harrison BH, Cooper RE: In vitro elution character- istics of commercially and noncom- mercially prepared antibiotic PMMA beads. Clin Orthop 1992;284:303-309. 15. Penner MJ, Masri BA, Duncan CP: Elution characteristics of vancomycin and tobramycin combined in acrylic bone-cement. J Arthroplasty 1996;11: 939-944. 16. Masri BA, Duncan CP, Beauchamp CP: Long-term elution of antibiotics from bone-cement: An in vivo study using the prosthesis of antibiotic- loaded acrylic cement (PROSTALAC) system. J Arthroplasty 1998;13:331-338. 17. Askew MJ, Kufel MF, Fleissner PR Jr, Gradisar IA Jr, Salstrom SJ, Tan JS: Effect of vacuum mixing on the mechanical properties of antibiotic- impregnated polymethylmethacrylate bone cement. J Biomed Mater Res 1990;24:573-580. 18. Davies JP, Harris WH: Effect of hand mixing tobramycin on the fatigue strength of Simplex P. J Biomed Mater Res 1991;25:1409-1414. 19. Morita M, Aritomi H: Bone cement not weakened by cefuzonam powder. Acta Orthop Scand 1991;62:232-237. 20. Marks KE, Nelson CL, Lautenschlager Thomas N. Joseph, MD, et al Vol 11, No 1, January/February 2003 47 EP: Antibiotic-impregnated acrylic bone cement. J Bone Joint Surg Am 1976;58:358-364. 21. Lautenschlager EP, Jacobs JJ, Marshall GW, Meyer PR Jr: Mechanical proper- ties of bone cements containing large doses of antibiotic powders. J Biomed Mater Res 1976;10:929-938. 22. Holtom PD, Warren CA, Greene NW, et al: Relation of surface area to in vitro elution characteristics of vancomycin- impregnated polymethylmethacrylate spacers. Am J Orthop 1998;27:207-210. 23. Masri BA, Duncan CP, Beauchamp CP, Paris NJ, Arntorp J: Effect of vary- ing surface patterns on antibiotic elu- tion from antibiotic-loaded bone cement. J Arthroplasty 1995;10:453-459. 24. Adams K, Couch L, Cierny G, Calhoun J, Mader JT: In vitro and in vivo evalua- tion of antibiotic diffusion from antibiot- ic-impregnated polymethylmethacrylate beads. Clin Orthop 1992;278:244-252. 25. Seligson D, Mehta S, Voos K, Henry SL, Johnson JR: The use of antibiotic- impregnated polymethylmethacrylate beads to prevent the evolution of local- ized infection. J Orthop Trauma 1992;6: 401-406. 26. Brien WW, Salvati EA, Klein R, Brause B, Stern S: Antibiotic impregnated bone cement in total hip arthroplasty: An in vivo comparison of the elution properties of tobramycin and van- comycin. Clin Orthop 1993;296:242-248. 27. Espehaug B, Engesaeter LB, Vollset SE, Havelin LI, Langeland N: Antibiotic prophylaxis in total hip arthroplasty: Review of 10,905 primary cemented total hip replacements reported to the Norwegian arthroplasty register, 1987 to 1995. J Bone Joint Surg Br 1997;79: 590-595. 28. McQueen MM, Hughes SP, May P, Verity L: Cefuroxime in total joint arthroplasty: Intravenous or in bone cement. J Arthroplasty 1990;5:169-172. 29. Hope PG, Kristinsson KG, Norman P, Elson RA: Deep infection of cemented total hip arthroplasties caused by coagulase-negative staphylococci. J Bone Joint Surg Br 1989;71:851-855. 30. Garvin KL: Two-stage reimplantation of the infected hip. Semin Arthroplasty 1994;5:142-146. 31. Carlsson AS, Josefsson G, Lindberg L: Revision with gentamicin-impregnated cement for deep infections in total hip arthroplasties. J Bone Joint Surg Am 1978;60:1059-1064. 32. Elson R: One-stage exchange in the treatment of the infected total hip arthroplasty. Semin Arthroplasty 1994; 5:137-141. 33. Raut VV, Orth MS, Orth MC, Siney PD, Wroblewski BM: One stage revision arthroplasty of the hip for deep gram negative infection. Int Orthop 1996;20: 12-14. 34. Raut VV, Siney PD, Wroblewski BM: One-stage revision of total hip arthro- plasty for deep infection: Long- term followup. Clin Orthop 1995;321:202-207. 35. Garvin KL, Salvati EA, Brause BD: Role of gentamicin-impregnated ce- ment in total joint arthroplasty. Orthop Clin North Am 1988;19:605-610. 36. Ure KJ, Amstutz HC, Nasser S, Schmalzried TP: Direct-exchange arthroplasty for the treatment of infec- tion after total hip replacement: An average ten-year follow-up. J Bone Joint Surg Am 1998;80:961-968. 37. Calton TF, Fehring TK, Griffin WL: Bone loss associated with the use of spacer blocks in infected total knee arthroplasty. Clin Orthop 1997;345:148-154. 38. Leunig M, Chosa E, Speck M, Ganz R: A cement spacer for two-stage revision of infected implants of the hip joint. Int Orthop 1998;22:209-214. 39. Hofmann AA, Kane KR, Tkach TK, Plaster RL, Camargo MP: Treatment of infected total knee arthroplasty using an articulating spacer. Clin Orthop 1995;321:45-54. 40. Fehring TK, Odum S, Calton TF, Mason JB: Articulating versus static spacers in revision total knee arthroplasty for sep- sis. Clin Orthop 2000;380:9-16. 41. Lai KA, Shen WJ, Yang CY, Lin RM, Lin CJ, Jou IM: Two-stage cementless revision THR after infection: 5 recur- rences in 40 cases followed 2.5-7 years. Acta Orthop Scand 1996;67:325-328. 42. Nelson CL, Evans RP, Blaha JD, Cal- houn J, Henry SL, Patzakis MJ: A com- parison of gentamicin-impregnated polymethylmethacrylate bead implan- tation to conventional parenteral antibi- otic therapy in infected total hip and knee arthroplasty. Clin Orthop 1993; 295:96-101. 43. Whiteside LA: Treatment of infected total knee arthroplasty. Clin Orthop 1994;299:169-172. 44. Hanssen AD, Rand JA, Osmon DR: Treatment of the infected total knee arthroplasty with insertion of another prosthesis: The effect of antibiotic- impregnated bone cement. Clin Orthop 1994;309:44-55. 45. Younger AS, Duncan CP, Masri BA, McGraw RW: The outcome of two- stage arthroplasty using a custom-made interval spacer to treat the infected hip. J Arthroplasty 1997;12:615-623. 46. Younger AS, Duncan CP, Masri BA: Treatment of infection associated with segmental bone loss in the proximal part of the femur in two stages with use of an antibiotic-loaded interval prosthe- sis. J Bone Joint Surg Am 1998;80:60-69. 47. Lynch M, Esser MP, Shelley P, Wroblewski BM: Deep infection in Charnley low-friction arthroplasty: Comparison of plain and gentamicin- loaded cement. J Bone Joint Surg Br 1987;69:355-360. 48. Otsuka M, Sawada M, Matsuda Y, Nakamura T, Kokubo T: Antibiotic delivery system using bioactive bone cement consisting of Bis-GMA/ TEGDMA resin and bioactive glass ceramics. Biomaterials 1997;18:1559-1564. 49. Korkusuz F, Uchida A, Shinto Y, Araki N, Inoue K, Ono K: Experimental implant-related osteomyelitis treated by antibiotic-calcium hydroxyapatite ceramic composites. J Bone Joint Surg Br 1993;75:111-114. 50. Gerhart TN, Roux RD, Hanff PA, Horowitz GL, Renshaw AA, Hayes WC: Antibiotic-loaded biodegradable bone cement for prophylaxis and treat- ment of experimental osteomyelitis in rats. J Orthop Res 1993;11:250-255. 51. Bohner M, Lemaitre J, Van Landuyt P, Zambelli PY, Merkle HP, Gander B: Gentamicin-loaded hydraulic calcium phosphate bone cement as antibiotic delivery system. J Pharm Sci 1997;86: 565-572. 52. Murakami T, Murakami H, Ramp WK, Hudson MC, Nousiainen MT: Calcium hydroxide ameliorates tobramycin tox- icity in cultured chick tibiae. Bone 1997; 21:411-418. 53. Calhoun JH, Mader JT: Antibiotic beads in the management of surgical infections. Am J Surg 1989;157:443-449. 54. Buchholz HW, Elson RA, Heinert K: Antibiotic-loaded acrylic cement: Cur- rent concepts. Clin Orthop 1984;190: 96-108. 55. Donati D, Biscaglia R: The use of antibiotic-impregnated cement in infected reconstructions after resection for bone tumors. J Bone Joint Surg Br 1998;80:1045-1050.