PROCEEDING OF N°243 COMMISSION PARITAIRE 1218T 86410 ISSN : 1148 2362 N° 243

UPDATE

PMMA BONE CEMENT: WHAT IS THE ROLE OF LOCAL ? Klaus-Dieter KÜHN1,2, Elke LIEB1,3, Christof BERBERICH1

1Heraeus Medical GmbH, Philipp-Reis-Str. 8/13, D-61273 Wehrheim 2Deptartment of Orthopaedic , Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria 3Klinik für Orthopädie, Center für Muskuloskeletale Chirurgie, Charité - Universitätsmedizin Berlin, Augustenburger Platz 1, D-13353 Berlin

INTRODUCTION sion implants. Because of cement really add benefit to European registries have the high initial release of the common practice of sys- shown longer survival data local antibiotics into the temic AB prophylaxis and to of cemented arthroplasty, joint cavity, ALBC has also AB treatment protocols in particularly when looking at Recently, PMMA bone been successfully used for cases of already established the endpoint revisions due cement has celebrated the decades for prophylactic prosthetic joint infections? to infection [1] (see Figure 50th anniversary of its cli- reasons aimed at prevention 1, 2). It has to be pointed nical use. During this time, of bacterial colonisation of Fortunately, prosthetic out, however, that important surgeons have appreciated the prosthesis. Gentamicin is joint infection (PJI) is a parameters, such as patient-, the product’s unique mecha- generally chosen because of rare pathology, but treat- pathogen- and treatment-re- nical properties for the fixa- the controlled diffusion out ment of the infection is lated risk factors can rarely tion of implants into joints of the cement mantle and often complex and increa- be compared across the and weak bone structures the broad spectrum bacte- singly difficult in view of different groups. Since larger leading to the long-term suc- ricidal effect against a wide the growing prevalence of randomised controlled clini- cess of joint prostheses after variety of gram-positive difficult-to-treat pathogens cal trials with ALBC invol- both primary and revision or gram-negative bacterial and higher patient risk fac- ving thousands of patients surgery. contaminants. However, in tors. Apart from the surgical with long clinical observa- times of increasing bacterial challenge and the impact on tion periods have not been Due to its primary fixation resistance, empiric use of the patient, PJI treatment performed, the clinical evi- purpose loaded antibiotics (AB) has become involves high costs which dence regarding its effica- bone cement (ALBC) has a controversial discussion are often more than twice cy and safety is still limited been classified as a class III point, and it appears justified the cost of an aseptic joint and is largely derived from medical device according to ask the following ques- replacement. the analysis of registries or to the CE standard for the tion: Does the addition of retrospective single-centre fixation of primary or revi- one or several AB to bone studies. UPDATE

To circumvent the problem the role and clinical evi- investigations have proven prostheses. The discussion of a low statistical power dences of ALBC in ortho- the non-toxicity of PMMA which technique is superior typically associated with cli- paedic surgery. in this indication. Thanks to is quite controversial, the nical studies of rare patholo- its outstanding compatibility more so as the decision of gies, so called surrogate mar- with human tissue, PMMA whether to use or not a bone kers and surrogate endpoints later found its place in the cement for fixation also de- are often used to evaluate the A MEDICAL fixation of femoral implants pends to a high extent on pa- efficacy of a particular treat- BLOCKBUSTER since the 1950s. tient factors [11]. However, ment concept. Therefore, in FOR A LONG it has been proven by many case of ALBC it has been TIME PMMA cement has now arthroplasty registries that proposed to evaluate their been successfully used in or- older patients (> 75 years) efficacy as local AB carrier in thopaedic surgery for more particularly benefit from than two generations. Its cemented prostheses as evi- addition to its fixation qua- Chemically, PMMA cement lity by assessing their poten- excellent biomechanical pro- denced by the lower num- is acrylic plexiglas made of perties have been evaluated bers of joint revisions [12]. tial to inhibit biofilm forma- PolyMethylMethAcrylate tion on the implant surface. in many scientific studies [2- Cementless total hip replace- (= PMMA). When this ma- 6]. The main role of cement ment (THR) is the preferred To provide an overview and terial was used in the 1940s to deepen the knowledge is to quickly stabilise the im- choice in young patients, al- in surgery for the first time, plant in bone tissue, improve though the fixation proce- of this concept, this review it was intended to fill gaps focuses in the following on the load distribution on the dure for such hip implants in the skull. Many clinical contact surface, fill and - le is often considered to be Uncemented THAs vel off the implant-bone more demanding and the ce- interface and also stiffen the mentless implants are more spongy bone around the im- expensive in comparison to plant. All these properties their cemented counterparts. improve the anchorage of In contrast to the overall the implant in bone, or more trend towards uncemented generally said, they improve THR, cemented fixation the ideal integration of a is still considered the gold foreign body in a biological standard in almost all total medium. replacements (TKR) worldwide, regardless of pa- Today, several million or- tient age [10,13]. thopaedic procedures are conducted worldwide and Since its introduction, more than half of them PMMA cement has been routinely use PMMA ce- combined with an AB agent, ments. Thanks to the ease which is in the majority of of use, but above all, thanks cases the aminoglycosides to the confirmed long-term gentamicin or tobramycin. Cemented THAs survivorship of cemented The first such commercial- implants, PMMA cement is ly available ALBC were in- recognised as a reliable and troduced in the 70ies in the well tolerated anchorage ma- market as pharmaceutical terial. The unique properties products. In order to fur- of PMMA cements ensure ther improve the function rapid and simple fixation of PMMA as a local drug of the joint implant, even in delivery system and to adapt patients with active osteopo- the anti-infective spectrum rosis. As proof of concept, to a special pathogen pro- international arthroplasty file, other AB than -genta registers demonstrate the ex- micin and combinations of cellent long-term outcomes at least two AB are often of a cemented prosthesis [7- added. Certain combinations 12, 107]. of AB are particularly inte- resting because of the syner- In most of these registers, gistic elution effect which Figure 1 & 2 Percentage revision due to deep infection, for uncemented THAs, and for cemented THAs, for 4 periods of primary surgery (x-axis: the results for cemented leads to a higher mutual AB years after operation, y-axis: cumulative revision rate in %) [1] prostheses are compared release. This holds true for with those for cementless e.g. vancomycin combined

2 // MAITRISE ORTHOPEDIQUE UPDATE with gentamicin [14, 15] and to the assumption that lo- sile bacterial phenotypes to that can anchor them to all clindamycin combined with cal AB in combination with AB and other antimicrobial kinds of material - metals, gentamicin [14]. The release systemic AB have a benefit agents. In addition, the slimy plastics, soil particles, medi- of the antibiotics from the (43,49,107, 108, 110). biofilm layers made of - car cal implant materials and outer cement mantle fol- bohydrates and proteins pro- necrotic tissue. The first lows the law of diffusion A broad range of gram-po- vide a safe habitat in which bacterial colonists to adhere and correlates directly with sitive and gram-negative the germs are physically and to a surface initially do so the hydrophilic properties bacteria have been identified chemically protected from by inducing weak, rever- of the cement polymers. For as causative agents of PJI. killing by the host immune sible bonds. If the colo- primary arthroplasties bone Although being rare cases, defence mechanisms [18]. nists are not immediately cement containing genta- even fungi, such as Candida, cleared from the surface, micin represents in most have been found as part of a Pathomechanisms of PJI: they can anchor themselves countries the gold standard polymicrobial infection flora Every surgical operation more permanently using for the local prevention of in immunocompromised pa- bears the risk of a bacte- cell adhesion molecules on prosthetic joint infections tients. Table 1 shows which rial contamination which their surfaces that bind other due its broad-spectrum and pathogens are most relevant may subsequently turn into cells in a process called cell strict concentration-depen- in PJI: an infection if not cleared. adhesion [19]. It is thought, dant antimicrobial effect. poses the that in the course of the fol- patient at a particularly high lowing hours the bacterial The main advantage of using BIOFILM risk for infections due to the pioneers facilitate the arrival PMMA as local delivery sys- FORMATION additional presence of the of other pathogens by provi- tem for AB is the finding implant or bone cement (if ding more diverse adhesion that the site of application AND BACTERIAL not loaded with AB) which sites. They begin to build the is the strict site of the effect. COLONISATION can be easily colonised. PJI is matrix that holds the bio- Pharmacokinetic studies OF IMPLANTS often associated with severe film together and transform have shown that an initially joint pain and often reduces into growth-retarded sessile very high and effective local patient mobility. In extreme forms. concentration of the AB is cases it may even lead to the obtained at the implant-ce- Most research into bacterial loss of a limb or even to In the presence of forei- ment-bone interface without pathogenesis has focused death if a generalised sep- gn material the minimum significant systemic burden historically on acute infec- tic situation evolves from number of microorganisms which is evident in the only tions, but these diseases have the local infection focus. In required to initiate a Staphy- transiently increased AB le- now been supplemented by all cases treatment of PJI is lococcus (S) aureus infec- vels in urine and serum. Ap- the new category of chronic associated with more exten- tion has been experimentally plying the same AB via oral infections caused by bacteria sive and time-consuming shown to decrease by more or intravenous route has, growing in slime-enclosed surgical interventions and than 100,000 times [20]. however, the exact opposite sessile aggregates known high costs. This can be partly explained effect with high concentra- as biofilms. Biofilm infec- by the lack of locally acting tions in urine and serum, but tions associated with chro- Biofilms form when bacteria granulocytes in the non-vas- only low AB levels in bone nic wounds and implants of e.g. the skin or intestinal cularised material [21]. In tissue and joint spaces, often or catheters affect millions flora contaminate the surgi- animal models the presence below the minimal inhibito- of people. The hallmark of cal site and start to adhere of 100 colony forming units ry concentration of a bacte- chronic biofilm infections is to surfaces in aqueous envi- of S. aureus was sufficient to rial pathogen [16]. The hi- the extreme resistance of the ronments. They subsequent- infect 95% of subcutaneous gher the concentration of an highly growth-retarded ses- ly excrete a slimy substance implants [22]. Although S. AB such as gentamicin, the better its bactericidal action and its capacity to deconta- minate the prosthesis and its surroundings from possible bacteria introduced into the surgical site. The observa- tion that high local concen- trations of some AB such as clindamycin may additio- nally eradicate intracellular persistent forms of Staphy- lococcus aureus in already established PJI cases [14] Table 1: Prevalence (%) of pathogens in periprosthetic implant infections [17] adds additional arguments

MAITRISE ORTHOPEDIQUE // 3 UPDATE aureus belongs to the more implant-carrier is, during suffering from other conco- virulent pathogens, simi- life-time, at a higher risk mitant diseases, and that two ANTIBIOTIC lar pathomechanisms also of an implant-infection as out of three patients sche- PROPHYLAXIS - exist for commensals of a consequence of haema- duled for knee joint replace- the human skin flora, such togenous seeding of bacteria ment surgery had more than SYSTEMICALLY as S. epidermidis or Pro- from remote infection sites. three comorbidities [35, 36]. pioni acnes, the latter being This can occur at any time The need for a biofilm-di- a grossly underestimated [32]. rected prevention strategy is Use of appropriate AB is pathogen in chronic low therefore biologically plau- key for a successful pre- grade joint infections [23, A direct relationship between sible and urgent [37, 38]. vention or treatment strate- 24]. the risk for PJI and the time gy of bacterial infections of the operation is evident. The high “vulnerability” of because of their specific Because of the biofilm-as- Therefore, revision surge- any implant for bacterial action against bacteria. All sociated life cycle, detec- ry leads to a higher number colonisation and the increa- medical guidelines empha- tion of such low virulent of PJI cases than primary sing demand for knee and sise the need to first identify bacterial pathogens is often arthroplasty following the serves to the pathogen and then take difficult in fluid or biopsies “rule” that the more the emphasise the importance the decision on the surgi- making the confirmation or vitality of bone and soft tis- of implementing strate- cal and antibiotic approach exclusion of a joint infec- sue is affected by previous gies to minimise the risk of to be adopted according to tion a real clinical challenge. revision(s), the higher is the infections. However, as long the type of intervention, the In particular, anaerobic infection risk. The presence as there is nothing commer- type of germ and the hos- Propioni acnes is often not of severe patient comorbi- cially available which may pital setting [39]. Despite detected, as its growth in dities, such as cardiovascular fulfil this aim, surgeons still this wide consensus a recent culture requires not only a disease, poorly controlled have to rely on “old” strate- study has shown that in at sufficient number of free glucose levels in diabetes gies for infection prevention, least 20% of cases therapy living (planktonic) bacte- mellitus or excess body which includes strict theatre is not in line with recom- ria in the specimen, but, in weight, also plays a major hygiene, quick operation mendations and about 40% addition, a significantly lon- role as risk factors in the times and appropriate syste- of hospitals do not properly ger incubation time of up to development of PJI [33, 34]. mic and local antibiotics. code the pathogen [33]. It is 14 days compared to “quick A study in the US showed obvious that improved dia- growers”. However, once that only 12% of joint repla- gnostic tools including for properly diagnosed, Propio- cement patients were not example the more and more ni acnes infections are not difficult to treat [23-30]. Dia- gnosis of PJI is further com- 100 plicated by the observation that some bacterial species, such as S. aureus, are able to completely change their phe- notype from planktonic into SC 95 highly growth-retarded, so C called small colony variant S (SCV) forms growing at an approximately 10 times N lower reproduction rate. Furthermore, mixed poly- 90 microbial infections which are increasing at an alarming trend in PJI with numbers exceeding 30% make the dia- gnosis and treatment even 85 more difficult [31]. 0 2 4 6 8 10 12 14 16 Years after surgery From these acute early or chronic delayed infections SC – systemic and in the cement C – in the cement which are mainly due to S – systemic perioperative contamina- N – no antibiotic tions, the category of acute late infections must be clearly distinguished. Any Figure 3: Norwegian Hip Registry: Lowest revision risk if combining both, systemic and local antibiotic prophylaxis. 4 // MAITRISE ORTHOPEDIQUE UPDATE used sonication technique of usual AB resistance rates follows in principle two bination of systemic and explanted prosthesis mate- among skin pathogens after rationales: first, from a local prophylaxis” (43, rial to dislodge bacteria from topical treatment. To circu- pharmacokinetic point 106, 109). It was found biofilms [37, 38, 40] enable a mvent this problem, tech- of view, both administra- that the revision rate was better treatment of in parti- niques and solutions such tion routes complement lowest in the latter group cular difficult-to-detect bac- as negative pressure therapy each other. Systemic AB (see Figure 3). Similar teria such as Propioni acnes. in wound care have been provide high concentra- results were also obtained encouraged as alternatives tions in serum and paren- from the Finnish knee Provided that the causative for topical antibiotics [44, chymateous organs while register concluding that microorganism is identified 46]. local AB released from no, or inappropriate local in PJI and the AB resistance PMMA provide high antibiotic prophylaxis, is and susceptibility profile of This concept, however, does concentrations in the an even higher risk factor the germs are known, even not apply for the musculos- otherwise difficult-to-ac- than no systemic AB pro- resistant bacteria can be effi- keletal system because of cess departments, such phylaxis (see Figure 4), ciently fought in the majority the high dose effect of local as bone tissue and joint (49, 51,52). of cases [32, 41, 42, 111]. AB in the bone and joint spaces, because of the However, this requires a compartments compared to poor vascularisation of Recent results from the close interaction between an the limited concentrations these tissues. Second, National Joint Registry infection disease specialist achieved here by systemically from an antimicrobial (NJR) of England, Wales and/or microbiologist and applied AB. Local adminis- efficacy point of view, and Northern Ireland (the the orthopaedic surgeon, in tration of active ingredients the mode and target of largest arthroplasty registry order to make the best deci- in these compartments may action of the systemic AB worldwide) add further sions on the type of AB, therefore be justified as (often a cephalosporin evidence to the efficacy of route and time of adminis- adjuvant prophylaxis and for prophylactic purpo- ALBC in the prevention of tration. The use of systemic treatment strategy and is, in se) is complemented by revision surgery. The data, as well as local AB completes fact, clinically relevant [17, the action of the amino- spanning the years 2004 – the surgical therapy which is 34, 47]. glycoside gentamicin or 2015, comprised 717,339 the radical debridement of combinations of it with cemented total knee and infected tissue. A recently published other AB. This does not 421,604 cemented total hip meta-analysis of available only widen the antimicro- arthroplasty procedures. Although being an essential clinical data has highlighted bial spectrum, but repre- Of those, 47% and 59% part in arthroplasty, the effi- the crucial role of ALBC in sents “two independent of primary hip and knee cacy of systemically adminis- lowering the risk for prosthe- security levels”, in case arthroplasties, respectively, tered AB against infections tic joint infection by up to the systemic AB prophy- were performed using Pala- in the bone and prosthesis 50% [48]. Similar conclu- laxis has not been given cos® R+G. A statistically interface is often limited as sions were also drawn from at the correct time and/ significant reduction in the a consequence of poor bone large European registry stu- or in the correct dose number of both hip and penetration. dies [43, 45, 49, 50]. In light prior to incision. The knee arthroplasty revisions of these observations it can local AB barrier may was observed when using be stated that PMMA-based also be effective in cases ALBC, specifically Pala- ANTIBIOTIC bone cement has proven of primary resistance of cos® R+G, compared to PROPHYLAXIS - clinical efficacy as a local bacterial contaminants to other bone cements (113), LOCALLY carrier of active ingredients the systemic antibiotic. (see Figure 5). acting as a surgical and phar- maceutical adjuvant. As proof of concept that Another recent data set the combination of both is derived from a French The topical application systemic and local AB cohort study with 100,200 of AB should be general- prophylaxis “works” best, patient data showing a ly considered with caution ANTIBIOTIC- can be considered the data clear association between because of the non-speci- LOADED PMMA from several arthroplasty total hip replacement cha- fic and difficult-to-control CEMENT (ALBC) registers. The Norwe- racteristics and the survi- mode of action which may gian hip register looked vorship of the implants. lead to an increased risk at the general revision Cemented THA, in gene- of antimicrobial resistance risk over an observation ral, did not only show a development. This has beco- The combination of sys- period of 16 years com- lower revision risk com- me evident in acne treatment temic and local AB to paring the risk of the pared to uncemented with AB-containing creams prevent implant-related group “no prophylaxis”, THA, but the use of or mupirocin-based MRSA infections and to sup- “systemic prophylaxis ALBC added an additio- decontamination strategies port the treatment of alone”, “local prophy- nal survival benefit to the often leading to higher than already established PJI laxis alone” and “com- MAITRISE ORTHOPEDIQUE // 5 UPDATE cemented hip implants (see Figure 6) [45]. 100

Last but not least, the 99 results from a recent randomised clinical trial 98 with 848 intracapsular neck fracture patients 97 in the UK have added strong evidence to which 96 extent a high dose double AB-loaded bone cement 95 is able to reduce the infection rate in high 94 risk patients. If the bone cement Copal® G+C 93 (containing 1g of genta- Survival rate without infection (%) micin and 1g of clindamy- 92 cin in 40g of cement) was used for cemented 91 hemiarthroplasty proce- dures instead of the low 90 dose cement Palacos® R+G (containing 0.5 g of gentamicin), the inci- 0 1 2 3 4 5 dence rate of superficial Follow-up (years) and deep infections was drastically reduced from Antibiotic prophylaxis 5.0% to 1.7% [53]. Antibiotic-impregnated cement only Combination: intravenous administration of antibiotics + antibiotic-impregnated cement Intravenous administration of antibiotics only Because of the favourable None clinical data for ALBC, many clinical guide- Figure 4: Adapted from Jämsen 2009 (49). The rate of reoperations for the treatment of infection was lowest when a lines including the most combination of intravenous antibiotic prophylaxis and prosthesis fixation with antibiotic-impregnated cement was used recent guideline issued by the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) [55, 107] recommend to consi- der the use of ALBC to reduce the incidence of prosthesis-associated biofilm infections.

Use of ALBC has also been common practice for long time for the fixa- tion of revision implants after two-stage revision procedures and for the manufacture of interim spacers in the time inter- val between the first and second stage as a strategy for the reduction of the risk of infection relapses.

As already mentioned, AB locally released from Figure 5: Registry results from the NJR 2015 comparing Palacos® R+G with other antibiotic-loaded bone cements 6 // MAITRISE ORTHOPEDIQUE UPDATE bone cement do not of the sessile bacterial against a variety of gram-posi- of diffusion from the material. result in a significant sys- phenotype (108). Eradi- tive and gram-negative bacteria The release of the active ingre- temic uptake of the active cation of biofilm bac- which are frequent in orthopae- dient is directly proportional to ingredient into organs teria is therefore a great dic infections. Bactericidal AB the water absorption capacity and body compartments challenge requiring the are clearly preferable because of (hydrophilicity) of PMMA and other than bone and joint complete explantation their rapid killing activity which also depends on the existing tissue [56, 57]. This can of the biofilm-conta- is not restricted to actively mul- surface area. All commercially be explained by the spe- minated prosthesis and tiplying germs. ABs with only available ALBC differ with res- cific kinetics of release cement followed by radi- a bacteriostatic activity are not pect to their polymer composi- of the antibiotic from cal surgical debridement suitable. tion and the production process the PMMA surface with of neighbouring bone leading to large differences with a high initial elution rate and soft tissue. To fur- Gentamicin, an aminoglycoside, respect to their antibiotic release followed by constant ther support the eradi- is the AB of choice in such low rates [6, 59, 112]. Figure 7 com- release over several days cation of the bacterial dose cements, as it perfectly ful- pares different AB release from [16]. An absolute prere- pathogens, the combina- fils this criteria. On the one hand commercially available bone quisite of the antimicro- tion of anti-biofilm-ac- it acts against a wide spectrum cements: bial effect of ALBC is a tive systemic AB, such as of germs including Staphylococ- local AB concentration rifampicin, and high-dose ci, Enterococci and Enterobac- A recurrent controversy is the well above the minimal local AB are then needed. teriacae targeting more than concern that the routine use inhibitory concentration 70% of the relevant pathogens of gentamicin-containing bone (MIC) and minimal bac- in PJI [16] with a strict concen- cement in arthroplasty might tericidal concentration tration-dependant bactericidal promote the development of (MBC) of those bacte- A CLOSER LOOK effect. On the other hand, it has bacterial resistance. Although ria which may cause PJI INTO ALBC USED an excellent elution profile from this cannot be completely ruled after implantation of IN PRIMARY the PMMA bone cement matrix. out - especially if using a bone the prosthesis. Low dose SURGERY Local gentamicin-induced cell cement matrix with low AB (0.5-1g of antibiotic) toxicity is of no concern at release capacity - this pheno- ALBC used in primary concentrations released from menon doesn´t appear to be of arthroplasty should in ALBC [16]. major clinical importance. Both, principle fulfil the requi- ALBC used in primary in Scandinavia and in Germany, rement to act as a coloni- arthroplasty are so-called low Studies show that the drug two regions where ALBC have sation barrier. However, dose antibiotic cements (typi- release rate is initially high and been in widespread use for many according to several in cally 0.5-1g of antibiotic per then declines after a few days. years, there is no indication of a vitro and clinical studies, 40g cement powder) containing Release from PMMA cement higher gentamicin resistance rate the quantity of eluted AB a broad spectrum AB active takes place according to the laws in the orthopaedic ward. Recent and the duration of the AB release vary signifi- cantly among different commercial brands of ALBC, thus suggesting careful selection of the brand of ALBC [3-5, 9, 12, 57-59].

Being a strict concentra- tion-dependant bacte- ricidal AB, the absolute concentration of gen- tamicin is an important parameter of its efficacy to prevent biofilm for- mation of even inter- mediate resistant germs in the “race for the sur- face” [60] together with the systemic AB prophy- laxis. Once a biofilm has been formed, the MIC is increased by a factor of at least 1000 because Figure 6: French cohort study: cumulative revision risk of total hip replacement according to cement type MAITRISE ORTHOPEDIQUE // 7 UPDATE

AB resistance mapping studies advocate for the best patient- that that high amounts of added concern when using high dose have even shown a trend to lower and germ-adapted treatment AB to the cement powder may ALBC for spacer manufacture. resistance rates of the germ S. approach [32, 44, 71]. compromise the mechanical sta- aureus to gentamicin [61]. The bility of the bone cement. It is Another strong argument for issue whether routine use of In contrast to low dose ALBC therefore critical not to exceed a high local concentration of ALBC in primary arthroplasty in primary procedures, such high a certain amount of added AB some particular AB has been favours AB resistance has also dose ALBC should contain an (typically max. 10% of cement provided by a recent study com- been addressed in a recent study AB (or better combinations of powder), if the cement is used paring the intracellular killing at one of the most active clinics AB) which allow the rational for the fixation of the revision activity of several AB. It was in the US regarding the number targeting of bacterial pathogens prosthesis. The mechanical shown that clindamycin exhibits of hip and knee replacement based on the prior antibiogram. aspects are not as much of a a potent antimicrobial effect on procedures. It was found that However, it must be pointed out intracellular S. aureus, suggesting the shift from plain cement to ALBC in 2003 had no impact on the number and pattern of AB resistancies of bacterial germs in the orthopaedic ward [62].

Consideration of all available clinical evidence, it must be concluded that ALBC has pro- ven its additional benefit in infection prophylaxis in primary arthroplasty [56, 63-65].

REVISION SURGERY AND TARGETED AB-LOADED CEMENTS

Septic revisions due to PJI are Figure 8 (adapted from Valour et al. 2015) [14] showing the antimicrobial activity of several AB against intraosteoblastic Staphylococcus aureus already a huge burden with inci- * = no action when used in monotherapy dence rates probably underesti- mated in the arthroplasty regis- ters [66-70]. Effective infection control with the aid of ALBC is therefore even more essential. Typically, high-dose AB cements (2g and more per 40g cement powder) are used in this indica- tion either for the anchorage for the revision prosthesis in one or two stage protocols or for the manufacture of ALBC spacers in the interim period of 2-stage protocols following the rationale, the more AB you add the more AB might potentially be eluted. Which of the surgical options is the best depends on the course of infection, the pathogen, the amount of bone loss and on further patient risk factors. A multi-disciplinary team including Figure 7: Comparison of antibiotic release from different commercially available PMMA cements. Blue bars indicate an infectious disease specialist content of antibiotic in cement powder in %, green bars indicate the overall release of the antibiotic within 7 days in and/or a microbiologist may % [6] 8 // MAITRISE ORTHOPEDIQUE UPDATE that this mainly bacteriostatic Manual Admixing of Antibio- vitro-antimicrobial efficacy have an infectious disease specialist AB at systemic concentrations tics to Bone Cement been found (see Figure 12) [86]. and/or a microbiologist may can become bactericidal when In view of the growing aIn view advocate for the best patient- delivered directly in local bone of the growing antimicrobial Another in vitro comparison and germ-adapted treatment environment (see Figure 8). resistance of pathogens invol- between commercially and approach [32, 44, 71]. ved in PJI it is obvious that manually mixed ALBC (Palacos Combination of Genta- AB-bone cement mixtures must R® as control, Palacos® R+G, In contrast to low dose ALBC micin and Vancomycin in sometimes be customised to the and Palacos® R with gentami- in primary procedures, such high ALBC specific germ profile. Multi-drug cin manually added) revealed dose ALBC should contain an resistancies do not only refer to that the inhibition zone for bac- AB (or better combinations of Methicillin resistant S. aureus MRSA/MRSE, but refer also terial growth was larger with AB) which allow the rational (MRSA) is an important factor more and more to gram-nega- the commercial ALBC cement targeting of bacterial pathogens of hospital morbidity and mor- tive bacteria and difficult-to-treat compared to the cement to based on the prior antibiogram. tality. Of equal or even higher polymicrobial infections. which the antibiotic had been However, it must be pointed out clinical concern is, however, the manually admixed [87]. Septic that that high amounts of added growing methicillin resistance As mentioned earlier, the iden- revisions due to PJI are already AB to the cement powder may rates of S. epidermidis (MRSE). tification of the causative orga- a huge burden with incidence compromise the mechanical sta- Current records indicate that nism and the assessment of rates probably underestimated in bility of the bone cement. It is MRSA/MRSE infections lead possible antibiotic resistance is the arthroplasty registers [66-70]. therefore critical not to exceed to significantly longer hospital of paramount importance for Effective infection control with a certain amount of added AB stays, higher costs and an overall a successful infection manage- the aid of ALBC is therefore (typically max. 10% of cement increase in mortality. ment. If it proves necessary to even more essential. Typically, powder), if the cement is used admix an AB to PMMA cement high-dose AB cements (2g and for the fixation of the revision In all those PJI cases in which in septic revision surgery, it is more per 40g cement powder) prosthesis. The mechanical a MRSA/MRSE pathogen recommended to contact a spe- are used in this indication either aspects are not as much of a has been identified, vancomy- cialist to ensure that the chosen for the anchorage for the revi- concern when using high dose cin-loaded PMMA cement antibiotic is sufficiently effective sion prosthesis in one or two ALBC for spacer manufacture. is the AB of choice for local with PMMA. An inadequate stage protocols or for the manu- administration during revision quantity may compromise the facture of ALBC spacers in the Another strong argument for arthroplasty. The highly syner- stability of the prosthesis or a interim period of 2-stage pro- a high local concentration of gistic effect of both AB genta- too low elution of the cement tocols following the rationale, some particular AB has been micin and vancomycin has been matrix may generate the emer- the more AB you add the more provided by a recent study com- well known to the infectious gence of resistant bacteria [19]. AB might potentially be eluted. paring the intracellular killing disease specialist for many years Which of the surgical options is activity of several AB. It was [15, 77-80]. Figure 10 shows the The AB powder must be soluble the best depends on the course shown that clindamycin exhibits time-kill curve of this synergism. in water and a maximum dose of of infection, the pathogen, the a potent antimicrobial effect on 4g per 40g of polymer powder amount of bone loss and on intracellular S. aureus, suggesting Again, it is highly recommended (10%) should not be exceeded if further patient risk factors. A that this mainly bacteriostatic to combine vancomycin with ALBC is used for fixation pur- multi-disciplinary team including AB at systemic concentrations gentamicin, as vancomycin alone pose. In case of ALBC used as diffuses very slowly out of the temporary spacer the mechanical The combined usage of Gentamicin and Clindamycin in COPAL® G+C cement matrix because of size, strength of the AB-cement mix- has a synergetic effect structure and the relative hydro- ture is of less importance [84]. It phobicity of this molecule [81]. must always kept in mind, that 100 COPAL® G+C Gentamicin 1,0 g/40 g The synergistic elution effect the manual addition of antibio- COPAL® G+C Clindamicin 1,0 g/40 g with gentamicin ensures a far tics can have a significant effect PALACOS® R+G Gentamicin better diffusion of vancomycin on the different mechanical (and gentamycin) leading to the properties of the cement [85]. strongest antimicrobial effect Inhomogeneous mixtures in 10 µg/ml against various MRSA strains particular reduce the stability of [6, 82, 83]. Figure 11 indicates the matrix and can significant- the efficacy of this combination ly reduce implant life span [6]. measured by the bacterial inhi- Similarly, it is difficult to predict bition zone for a “wildtype” S. any synergy and antagonism in 1 aureus (methicillin-sensitive) and terms of diffusion. When direc- 0 1 2 3 4 5 6 7 8 9 10 different clinical MRSA isolates tly comparing manually AB-ad- Days over a period of 7 days. mixed bone cement with indus- Figure 9: Synergy of elution of the antibiotics gentamicin (G) and clindamy- trially manufactured commercial cin (C ) from Copal® G+C compared to the gentamicin elution from Pa- ALBC differences regarding lacos® R+G cement samples in vitro over a period of 10 days (Heraeus antimicrobial elution rate and in Medical GmbH data) MAITRISE ORTHOPEDIQUE // 9 UPDATE can become bactericidal when the antibiogram reveals sensi- gistic effect of both AB genta- strongest antimicrobial effect delivered directly in local bone tivity of the germ(s) for genta- micin and vancomycin has been against various MRSA strains environment (see Figure 8). micin and clindamycin, but also well known to the infectious [6, 82, 83]. Figure 11 indicates in high risk patients where the disease specialist for many years the efficacy of this combination Combination of Genta- risk of infection is significant- [15, 77-80]. Figure 10 shows the measured by the bacterial inhi- micin and Clindamycin in ly higher than normal. Another time-kill curve of this synergism. bition zone for a “wildtype” S. ALBC indication for use could be those aureus (methicillin-sensitive) and revision cases where the diagno- Again, it is highly recommended different clinical MRSA isolates Gentamicin and clindamycin sis is difficult and «uncertain» to combine vancomycin with over a period of 7 days. combined in bone cement act (e.g. culture-negative PJI cases) gentamicin, as vancomycin alone synergistically with respect to the or in those situations where diffuses very slowly out of the Manual Admixing of Anti- spectrum of antimicrobial action anaerobic bacteria such as Pro- cement matrix because of size, biotics to Bone Cement [14]. This combination also tar- pioni acnes cannot be ruled out. structure and the relative hydro- gets anaerobic bacteria which are phobicity of this molecule [81]. In view of the growing antimi- gaining growing importance as Another hallmark of AB com- The synergistic elution effect crobial resistancies it is obvious PJI pathogens, as well as strep- binations is the observation that with gentamicin ensures a far that AB-bone cement mixtures tococci often found in late hae- the presence of two AB with better diffusion of vancomycin must sometimes be customised matogenous infections. Another different modes of action vir- (and gentamicin) leading to the to the specific pathogen profile clear advantage of this AB com- tually rules out the risk of deve- bination is its synergistic effect lopment of concomitant resis- via a mutually increased elution tance to these two substances. from the PMMA matrix [6, 14, 72, 73] (see Figure 9). Because Despite the high local concen- of their high local diffusion, tration of both AB, systemic the concentration of these two side effects are not a concern AB gentamicin and clindamycin as evidenced by a clinical study is significantly higher than the showing that gentamicin and minimum inhibitory concentra- clindamycin peak only tran- tion (MIC) and minimum bac- siently in serum and urine after tericidal concentration (MBC) local use of Copal G + C and for several days and weeks at then quickly fall below detec- the surface of the cement [73, table levels [73]. Infection was 74]. In addition, being a rather resolved in all analysed patients small sized molecule, clindamy- during the observation period of cin shows excellent bone pene- one year. tration and exerts an intracellular bactericidal activity [14]. Combination of Genta- Figure 10: Time-kill curve of MRSA to gentamicin and vancomycin alone micin and Vancomycin in or a combination thereof demonstrating a strong synergism of antimicrobial As proof of concept for the ALBC efficacy of the combination [15] clinical benefit of such a syner- gistic high release profile of Methicillin resistant S. aureus two AB serve the observations (MRSA) is an important factor that 1. the Copal® G+C bone of hospital morbidity and mor- cement is more effective against tality. Of equal or even higher biofilm formation than Pala- clinical concern is, however, the cos® with only gentamicin [75] growing methicillin resistance and 2. the incidence of superfi- rates of S. epidermidis (MRSE). cial and deep infections is mar- Current records indicate that kedly reduced in the presence MRSA/MRSE infections lead of this double-loaded cement to significantly longer hospital if hemiarthroplasty procedures stays, higher costs and an overall in intracapsular neck fracture increase in mortality. patients were done with Copal® G+C instead of Palacos® R+G In all those PJI cases in which [53, 76]. a MRSA/MRSE pathogen has been identified, vancomy- In light of the clinical data, this cin-loaded PMMA cement Figure 11: Antimicrobial efficacy of Copal® G+V as measured by bacterial AB combination can therefore is the AB of choice for local the inhibition test zone against clinical MRSA isolates (University hospital of be recommended not only in all administration during revision Graz, Austria). MRSA 02/260 (G 64R, 1I-V R) MRSA 02/39 (G> those septic revision cases where arthroplasty. The highly syner- 256R, V 0.75s), MRSA 02/221 (G 48R, 1I V-R) 10 // MAITRISE ORTHOPEDIQUE UPDATE involved in PJI cases. Multi-drug cin manually added) revealed The impact of local ABs on ved at the site of infection can resistancies do not only refer to that the inhibition zone for bac- a two-stage interim PMMA be much higher than that achie- MRSA/MRSE, but refer also terial growth was larger with the cement spacer was analysed vable with systemic therapy, wit- more and more to gram-nega- commercial ALBC cement com- during a prospective clinical hout significant toxicity [98, 99]. tive bacteria and difficult-to-treat pared to the cement to which study conducted with 68 patients polymicrobial infections. the antibiotic had been manually presenting acute infection of the Taken together, this data suggest admixed [87]. hip prosthesis (all patients with that the placement of a spacer As mentioned earlier, the iden- fistula formation; gram-positive with high dose antibiotics (gen- tification of the causative orga- bacteria were detected in 68.5% tamicin and vancomycin) after nism and the assessment of pos- WHICH PMMA of all infections and gram-nega- removal of the infected implant sible antibiotic resistancies is of SPACER FOR tive bacteria in 31.5%). 30 of the and debridement of the joint paramount importance for suc- TWO-STAGE 68 patients were treated during cavity can significantly reduce cessful infection management. the intermediate period after the risk of reinfection (Figure If it proves necessary to admix REVISION removal of the infected prosthe- 13). an AB to PMMA cement in sep- SURGERY? sis without spacer (Girdlestone tic revision surgery, it is recom- resection) and 38 patients were Special PMMA spacer cements mended to contact a specialist to treated with an ALBC spacer with low-abrasive calcium car- ensure that the chosen antibio- Two-stage revision protocols treat the (with 1g of vancomycin/40 g). bonate/calcium sulphate used tic is sufficiently effective with joint infection by using a temporary The infection recurrence rate in as a contrast medium for radio- PMMA. An inadequate quantity ALBC spacer as a temporary prosthesis the Girdlestone group was par- logy, exhibit a markedly reduced may compromise the stability of before insertion of the definite revision ticularly high after primary sur- abrasion of cement particles the prosthesis or a too low elu- implant [5, 88]. gery with 23.3% versus 5.2% in during the intermediate period tion of the cement matrix may the group with spacer [97] (see (see Figure 14). The lower visi- generate the emergence of resis- Apart from local high AB elution, Figure 12). This result confirms bility of calcium carbonate on tant bacteria [81]. articulating ALBC spacer also allow a prior studies suggesting that the X-rays compared to conven- temporary joint function. By this, tis- local concentration of AB achie- tional contrast agents such as The AB powder must be soluble sue retraction is avoided and the joint in water and a maximum dose of space maintained, which often facili- 4g per 40g of polymer powder tates the subsequent implantation of (10%) should not be exceeded, if the revision prosthesis [82, 83, 86, 89, ALBC is used for fixation pur- 90]. An at least partial joint function pose. In case of ALBC used as is not possible with a non-articulating temporary spacer the mechanical spacer which is still in use. With respect strength of the AB-cement mix- to the efficacy of infection eradication ture is of less importance [84]. It differences between articulating and must always kept in mind, that non-articulating spacers have not been the manual addition of antibio- observed [91]. tics can have a significant effect on the different mechanical Articulating PMMA spacers are properties of the cement [85]. subjected to a specific cement Inhomogeneous mixtures in friction leading to abrasive Figure 12: Comparison of the release of gentamicin over 16 h from CMW particular reduce the stability of cement particle wear. Such par- and PALACOS bone cement after manual and industrial addition of the gentamicin (mean value of 3 separate bone cement samples)[86] the matrix and can significant- ticle wear can have a negative ly reduce implant life span [6]. impact on the future re-implan- Similarly, it is difficult to predict tation of a prosthesis leading 100 any synergy and antagonism in for example to a higher risk of terms of diffusion. When direc- subsequent revision implant 80 tly comparing manually AB-ad- loosening. It is also discussed if mixed bone cement with indus- particle wear in an inflamed and 60 trially manufactured commercial previously infected environment ALBC differences regarding leads to a “circulus viciosus” of 40 antimicrobial elution rate and in increased cell apoptosis [92-94], Recurrence of infections (%) vitro-antimicrobial efficacy have as it is well known that wear par- 20 been found (see Figure 12) [86]. ticles constitute a risk factor for 0 infection [95]. Therefore, not With ALBC spacer Without ALBC spacer Another in vitro comparison only the implant, but also wear between commercially and particles may interact with gra- Figure 13: Results of a prospective clinical study showing the impact of manually mixed ALBC (Palacos nulocytes that are involved in the treatment approach (with or without a vancomycin-loaded PMMA R® as control, Palacos® R+G, such a scenario [96]. hip-spacer in the interim-phase of a two-stage protocol) as measured by the and Palacos® R with gentami- reinfection rate [97] MAITRISE ORTHOPEDIQUE // 11 UPDATE zirconium dioxide and barium can create maximum benefit and primary hip replacement is cost-ef- has reacted to these challenges sulphate, is not a major concern, output with a limited budget. fective if assuming a significantly by developing bone cements since the lower visibility of cal- lower PJI incidence rate and costs with tailored antibiotic combina- cium carbonate is compensated Many countries try to control for the treatment of septic revision tions aimed at targeting different for by the large size of the spa- their health spending with case being approximately 3.5 times germ profiles. cer. methods that require calculations higher than the primary interven- In addition, because of the signi- to show the relationship between tion [105]. ficantly higher hydrophilicity the differences in the average of such a cement matrix, these costs of a technology compared spacers elute antibiotics much with the best alternatives. The CONCLUSION better than “conventional” bone consequences not only in «physi- cement spacers. cal terms» must therefore be mea- sured with a cost-effectiveness analysis (CEA), but a cost-utility Gaining deeper knowledge ECONOMIC analysis (CUA) is required for a about the properties and the IMPACT OF valuation of individual assess- application of bone cement is ALBC ments of the consequences. This of paramount importance to all is expressed in QALY units mea- orthopaedic surgeons. Although ning health related quality adjusted bone cement had been consi- life years. This corresponds to dered for a long time as a key In view of the predicted ageing a weighting of the time passed in the field of joint of the world’s population and the in good health (= utility). The replacement surgery, its use has changes in lifestyle factors, such results of cost-utility studies have somewhat decreased because as increased obesity and lack of so far not been a decisive factor of the introduction of press-fit physical activity as a consequence for access to treatment reimbur- implants which encourage bone of urbanisation and motorisation, sement. However, this kind of in-growth. The main purpose of it is estimated that the number of analysis is becoming increasingly bone cement is still a long-las- people affected by musculoskele- important for medical payers. ting fixation of prostheses. Since tal disorders and the numbers of AB elute relatively well from subsequent joint replacement sur- In Australia for instance ALBC PMMA, it must also be consi- geries will drastically increase. In was the subject of an incremen- dered as a modern drug delivery the United States alone, a doubling tal cost effectiveness ratio analysis system that delivers the required of the number of arthroplasty (ICER). The result of the compa- drugs directly to the surgical procedures is possible by 2030 rison between systemic AB the- site. In view of the increasing [100]. The overwhelming suc- rapy with and without concomi- challenges of more resistant cess of arthroplasty is evident tant use of ALBC revealed a gain bacterial pathogens and higher by the high patient satisfaction of 32 QALY equivalent to a sum patient risk factors, the antibiotic scores and the long life span of of AUD$ 123,000 [104]. A simi- carrier function gains additio- prostheses with 88-95% of the lar result was obtained in a study nal importance to prevent the primary implants still functioning in the UK comparing AB cement formation of bacterial biofilms well after 10 years [101, 102]. with plain cement. ALBC used and to suppress the incidence of for local prophylaxis resulted in infection relapses. The industry Complications of arthroplasty £37,355 per QALY [105]. procedures are rare [17]. However, surgeons and patients are increa- Preventing deep SSI with AB pro- singly faced with the problem of phylaxis and ALBC has shown implant-associated infections. The to improve health outcomes, consequences for patients and save lives, and enhance resource for the health service budgets are allocation [45]. The observation dramatic, mainly because of the that the use of high dose genta- longer hospital stays which often micin- and clindamycin-loaded exceed 30 days compared to only bone cement not only reduces the a few days in primary or aseptic rate of superficial and deep SSI in revision procedures [103]. Also, hemi-arthroplasty procedures, but the re-operation rate increases also reduces the number of days sharply, if the first infection inter- in ICU from 18 days to 3 days can vention fails. A crucial point in be considered of major health eco- health economic evaluations is to nomic impact [76]. Another cost/ Figure 14: Comparison of the abrasion of articulating tibial surfaces between analyse how medical interventions benefit study (level II evidence) Palacos® R (left picture) and Copal® Spacem-manufactured PMMA spa- showed that the use of ALBC in cers after 240,000 cycles, simulation after 3 months. 12 // MAITRISE ORTHOPEDIQUE UPDATE

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Implant Summary Report for Heraeus Medical Hips & using Heraeus Palacos Antibiotic Cement, NJR Database extract, 12/02/2015.18:43, © 2014 Northgate Information Solutions Ltd.

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