Antibiotics and Cement





Introduction


The use of antibiotics in cement predates the widespread use of systemic intravenous antibiotics for perioperative prophylaxis. In the 1950s, published data recommended avoiding administration of systemic antibiotics with the fear that they may actually increase infection rates. , The debate over utilization of antibiotics perioperatively continued into the 1970s. Intriguingly, while controversy about systemic perioperative antibiotic prophylaxis continued, local antibiotic mixture into the cement for arthroplasty fixation, for the same reason of infection prevention, had been well documented. By 1974, a series of 1119 total hips in Hamburg had been followed using the routine mixture of antibiotic cement with a deep infection rate of 0.1%, which was significantly lower than contemporary rates.


The foundations on which are built the type of cement and antibiotic impregnation used to maximize infection-free success are far from standardized. The reason for this lack of clarity is the wide variety of presenting scenarios, patients, and bone and soft-tissue statuses. Today, as periprosthetic joint infections (PJIs) are treated with a combination of systemic and local antibiotic delivery and both have significant contributions to effectiveness and toxicity, it is still important to focus attention on how surgeons can maximize this therapeutic ratio through the orthopaedic construct.


The existing literature is composed of an enormous collection of varying quality articles, often supporting and corroborating the findings of one another but also at times seemingly providing directly conflicting data. While there is a significant wealth of experience with this technique, the optimal antibiotic dosing/structural (cement) carrier/surgical construct, if one exists, remains elusive.


Polymethylmethacrylate (PMMA)


PMMA is the most common formulation of bone cement used in total joint arthroplasty (TJA). Preparation of PMMA consists of a polymer powder and a liquid monomer mixed in a typical 2:1 polymer-to-monomer ratio. This mixture creates an exothermic reaction on the order of 130 kcal/g of liquid ( Fig. 29.1 ).




Fig. 29.1


Polymerization of methyl methacrylate in cement used in orthopaedics.


Monomer Liquid


The liquid component is a standard, low-viscosity colorless fluid that carries a characteristic odor. It consists of several key components: (1) 97% to 99% monomeric methylmethyacrylate; (2) N,N-dimethyl-p-toluidine, which is 0.4% to 2.8% by weight and is a chemical reaction accelerator; and (3) a trace amount of hydroquinone in the monomer, which stabilizes the methylmethacrylate, preventing spontaneous polymerization.


While various techniques exist for local antibiotic delivery, PMMA as a carrier is convenient, can be cost-effective, and has been time tested. However, limitations exist. As the amount of antibiotic introduced into dry polymer mixture approaches 10%, the biomechanical strength of the resulting antibiotic cement significantly decreases. The likelihood of spacer failure (specifically, breakage) is not only related to the biomechanical strength of the cement but also is related to the patient’s weight, activity level/lifestyle, and, importantly, the duration of spacer treatment. These factors should be carefully weighed for the specific treatment plan formulation. A 15% by weight cement spacer has lasted as long as 7 years before breaking. Thus, the entire clinical picture should be assessed. It is also worth noting that in this mentioned case, significant bone loss was also encountered throughout the cement spacers implanted duration; thus, the effect on both the cement and host should be considered.


Polymer Powder


The other part of the mixture is the polymer powder. This contains prepolymerized solid particles of polymethylmethacrylate microspheres, which accounts for 83% to 99% of the powder. The powder also contains radiopacifiers, which include barium sulfate (10%) in the case of Simplex (Stryker, Mahwah, NJ), and zirconium oxide (15%) in Palacos (Heraeus, Hanau, Germany). Finally, the powder also contains the initiator, which is 1% dibenzoyl peroxide. This initiator destabilizes the double bond on methylmethacrylate, causing a free radical, which allows the linkages of molecules.


Curing


The process of preparing bone cement consists of four main phases. In the mixing phase, the polymer powder and monomer liquid are manually whisked to create a homogenous mixture. The sticky phase occurs immediately after mixing, characterized by a thick viscous liquid that is pourable and difficult to handle due to its propensity to stick to its contacts. It then transitions into the working phase, in which the cement is more doughy in consistency, and chemical polymerization has commenced. This is the stage in which molding, manipulation, and implantation occurs. Finally, in the hardening phase, the cement can no longer be molded and the exothermic reaction culminates in a significant release of heat. Most commercially available cements harden in 10 to 20 minutes depending on their formulation and viscosity ( Table 29.1 ).



TABLE 29.1

Most Commercially Available Cements Available (PMMA)






















































Vendor Product Line Viscosity Available Premixed Antibiotics
Biomet Bone Cement R High Gentamicin
Depuy Smartset Medium/High Gentamicin
DJO Cobalt Medium/High Gentamicin
Exactech Cemex Extra Low/Low/High Gentamicin
Heraeus Palacos Low/Medium/High/Fast Gentamicin
Medacta MectaCem Low/Standard Gentamicin
Microport OrthoSet Low/High None
Smith & Nephew Rally Medium/High Gentamicin
Stryker Simplex Medium/High Gentamicin or tobramycin

PMMA, Polymethylmethacrylate.


Viscosity


Bone cement is available in various different formulations, and one consideration is viscosity. Common options are low-, medium-, and high-viscosity cement. Low-viscosity options are characterized by a long sticky phase with a short working phase, are used in applications such as kyphoplasty, and are less commonly used in TJA. Medium-viscosity cement also has a relatively long sticky phase, although the working time is increased due to the slower rate of polymerization. High-viscosity cement has a short sticky phase and a long working phase, with a relatively constant viscosity. The latter two variants are more commonly used in TJA.


Biomechanical Properties


PMMA is strongest in compression and weakest in tension and under shear stress. Overall, it is a brittle material but less brittle in vivo due to the plasticizing effect of the surrounding biologic fluid. It has a Young’s modulus of elasticity that is just between cortical bone and ultra-high molecular weight polyethylene/cancelleous bone. Therefore, it is useful in the application of structural spacing at joints.


Duration of Local Antibiotic Treatment


The optimal duration of antibiotic spacer treatment is not well understood. In one basic science study, 6 weeks after antibiotic spacer treatment, periarticular membrane tissue was extracted and analyzed by mass spectrometry; concentrations of vancomycin, tobramycin, and clindamycin were all detected above their minimal inhibitory concentrations. However, clinical studies have cast doubt on whether antibiotics in cement are eluted beyond the first several days/week of implantation. In a PROSTALAC ( prost hesis with a ntibiotic- l oaded a crylic c ement) study, 3.6 g of tobramycin mixed per 40 g of cement was detectable at 118 days, whereas 2.4 g of tobramycin was not, suggesting that three vials of tobramycin per pack of cement is necessary if prolonged elution over the course of a 3-month period is desirable. Duration of vancomycin elution was inferior to tobramycin. While prolonged elution into the joint space is desirable, systemic absorption is a by-product and can cause remote toxicity (see Toxicity section that follows). Therefore, the elution profile is inherently linked with the starting concentration of antibiotics, which is also limited by biomechanical constraints of construction preparation.


As biomechanical and elution profiles are kept in mind for temporary spacers, spacer retention warrants consideration in some cases. Although conventional two-stage revision TJA for infection remains the standard of care for most PJIs, this treatment comes with significant morbidity, disruption of life, and decrease in overall functional outcome. As such, spacer retention is an attractive option, when appropriate, and evidence suggests it may be appropriate in certain scenarios. If spacer retention is to be a standard option at the surgeon’s disposal, prolonged antimicrobial activity and biomechanical durability are essential considerations.


Two common commercial forms of PMMA bone cement are Simplex and Palacos. Head-to-head in vitro comparisons of Simplex and Palacos with respect to the delivery of tobramycin and vancomycin showed that Palacos has a superior antibiotic elution profile. At high loads of antibiotic impregnation, eluates from Palacos cement also demonstrated two to three times longer duration of detectable bioactivity.


Modifications


Laboratory investigations have been performed to identify modifications to PMMA that will facilitate antibiotic delivery. Most of these modifications are experimental and not in widespread use. However, simple modifications, such as creating indentations in the cement, have been reported to increase drug delivery. Powdered vancomycin (2 g) applied to the surface of Palacos cement just prior to hardening for cement spacers or second-stage revision implants resulted in enhanced local delivery without systemic side effects or renal toxicity.


Chemical additives, such as citric acid and bicarbonate, have also been shown to increase elution. Hydroxyethylmethacrylate phosphate (0.5%) added to PMMA increased the elution of tobramycin by up to 50% in vitro without compromising its mechanical properties. More recently, the addition of polylactic-co-glycolic acid (PGLA) and biodegradeable microparticles were shown to enhance the elution of antibiotics from commercial cement while preserving adjacent bone integrity. , Such modifications may be helpful in situations in which cement mechanical strength and high antibiotic elution rates are both desirable. PGLA is used in other therapeutic devices approved by the US Food and Drug Administration owing to its biodegradability and biocompatibility.


The omission of hard radio contrast agents such as barium sulfate from PMMA also enhances microporous structure, improves antibiotic elution, and improved the tribology characteristics of the articulating spacer in a study of Copal (Heraeus; Hanau, Germany) cement spacers.


The authors do not believe that there is a high level of evidence supporting any of these modifications. In light of the satisfactory elution profiles of multiple agents in standard formulations of commonly used commercially available cements, more research is necessary to justify the introduction of these modifications. In addition, the effect on the biomechanical properties of the cement must be taken into account.


Cement Preparation—Surgeon Molded Versus Prefabricated


A comparison of cement with hand-mixed vancomycin (1–4 g) to commercial premixed tobramycin (1 g) showed that hand-mixed spacers are effective for cement spacers with higher concentrations of antibiotic delivery, but have inferior mechanical strength for second-stage or primary cemented components.


Storage


Storage of prefabricated spacers at 25° C, 4° C, or –20° C for 2 weeks or 3 months had no effect on vancomycin release into buffered saline as determined in vitro through liquid chromatography.


Alternative Carriers


While local antibiotic delivery has traditionally focused on impregnating the cement with antimicrobials, one alternative approach is to directly conjugate the antibiotic to the metal surface. Several groups have described treating a titanium alloy to create directly conjugated daptomycin, either through covalent bisphosphonate or a more facile thioester linkage. , In vitro, these foil conjugates exhibit potent bactericidal properties even against high concentrations of Staphylococcus aureus. It remains to be seen whether these surfaces are suitable for articulating surfaces, whether these covalent linkages/antibiotics are compromised by cyclical loading over a lifetime, and whether manufacturing of these surfaces on implants is even feasible. While daptomycin is a notoriously expensive reagent, similar studies have been performed with covalently linked vancomycin, which is bacteriostatic, showing inhibition of bacterial colony growth.


Another alternative approach may be to utilize a carrier other than PMMA. PMMA, as mentioned, is an attractive medium because it is an effective link between implant and bone and can elute antibiotics. However, other delivery carriers exist. Calcium sulfate, although possessing insufficient biomechanical strength to serve the same structural role of PMMA, has been shown to have superior vancomycin elution characteristics in vitro. These may be introduced as beads, pellets, or intramedullary blocks. Calcium hydroxyapatite/sulfate carriers used in combination with PMMA have also demonstrated promise in enhancing local delivery. The advantage that these alternate carriers provide is to increase local delivery without the requisite compromise in cement biomechanics that is inherent in using PMMA as the carrier. Additionally, calcium sulfate is resorbable and does not itself require extraction. While calcium sulfate has been suggested to have favorable long-term elution, providing a persisting antimicrobial effect, there is no evidence that this translates to enhanced infection eradication rates to our knowledge. In addition, for purposes of temporary spacers, many antibiotics can be introduced through PMMA at concentrations high enough to cover 3 months without compromising cement integrity, as discussed later (see Duration of Elution section to come). These beads can be distributed throughout the joint and in the intramedullary canals for enhanced delivery.


Descriptions of “hybrid” carriers exist—for instance, using a PMMA core for biomechanical strength, while coating on the periphery with calcium phosphate, which has a higher eluting potential than PMMA. These types of techniques are not in widespread use.


Antibiotic-Loaded Bone Cement


While the routine use of antibiotic-loaded bone cement (ALBC) in primary total knee arthroplasty (TKA) does not appear to lower infection rates in patients who are not high risk, its use in two-stage revision arthroplasty for PJI has a large body of evidence to support its use. Thus, ALBC is standard practice in today’s management of PJI. A meta-analysis of 11 articles comparing ALBC and non-ALBC found no difference in infection rates in primary TKA. However, there was a significant decrease in PJI in the setting of revision TKA when ALBC was used.


Choosing Antibiotics


To be used as an additive in PMMA with subsequent elution in vivo, an antibiotic must possess several properties. It must be heat stable and able to withstand the exothermic reactions involved in cement curing; it must be able to be mixed into the polymer powder form of PMMA; it must not be deactivated by PMMA and vice versa; and it has to have elution properties out of cured cement (i.e., be water-soluble). Antibiotics that can be used in PMMA are listed in Table 29.2 .



TABLE 29.2

Antibiotics That Are Heat Stable for Use in PMMA Cement


































Amikacin Daptomycin Levofloxacin Penicillin G
Cefoperazon Erythromycin Meropenem Tobramycin
Cefazolin Fosfomycin Moxifloxacin Tetracycline
Cephalothin Vancomycin Neomycin
Cefotaxime Fusidic acid Ofloxacin
Di/Cloxacillin Gentamycin Oxacillin

PMMA, Polymethylmethacrylate.


Heat Stability


The choice of antibiotics in loading cement must be restricted to those that are heat stable. Heat-stable antibiotics were historically tested by those that retained antimicrobial activity after a sterilization cycle of 15 minutes at 121° C. However, this temperature/duration is not what is typically found in the setting of cement curing in PJI cases. While peak temperatures of Simplex and Palacos can reach 110° C and 103° C, respectively, in the proximal tibia, these temperatures are not sustained for 15 minutes and have been found to be significantly lower at other locations of spacer molds. Therefore, while heat stability of specific antibiotics has historically limited their use to a few select predominant agents, less commonly used antibiotics, such as ceftazidime, can also be considered heat stable for the purposes of impregnating cement.


Heat-Stable Antibiotics in PMMA


Formulation


For an antibiotic to be loaded into cement, the structural requirement of the cement must be factored in. If it is to be used as a weight-bearing construct, the effects on the biomechanical properties of the antimicrobial on the cement are of paramount importance. Liquid formulations of antibiotics have historically been avoided because studies showed that the liquid mixed with PMMA decreased the biomechanical strength of PMMA by 30% to 50%. , Indeed, liquid gentamicin decreased PMMA compressive strength by 49% and tensile strength by 46%. Therefore, its use in PJI cannot be recommended. If the PMMA is not being used for its structural/biomechanical properties—for example, as used in drug-eluting cement beads—then liquid gentamicin formulation could warrant consideration based on its significantly lower cost (about 1% of the cost of the powder form).


Elution/Mixing Technique


While biomechanical strength of cement is desirable in definitive TJA in temporary antibiotic spacers, a trade-off between the strength of the cement and the concentration and elution of antibiotics exists. Not only does increasing the dosage of antibiotics in the cement directly weaken the cement, but the porosity of cement also enhances the elution profile. Therefore, the advanced cement preparation techniques that reduce porosity, including vacuum mixing and pressurization, may adversely affect antibiotic elution. This most likely relates to the amount of surface area on a microscopic level as well as on a macroscopic level (see Cement Beads section that follows). Nevertheless, cement preparation is commonly carried out by hand mixing or with a drill whisk, without vacuum, to preserve cement porosity.


Most commonly, antibiotic in powder form is mixed with the powder form polymer PMMA prior to the addition of monomer in an effort to homogenously mix the antimicrobial reagent evenly throughout the cement prior to the addition of the initiator/accelerant. However, the powdered mixture is often clumped and careful homogenous mixing is often laborious or compromised. Antibiotic powder may also be added in the liquid phase of cement preparation, after monomer addition, without significant impact on distribution through the cement. This sequence of mixing the cement polymer with the monomer, followed by antibiotic powder while the cement is liquid, has been described to facilitate hand mixing. No statistical differences have been observed in antibiotic distribution with this sequence. ,


Cement Beads


Cement beads or chains have the advantage of not being utilized as structural or weight-bearing portions of the construct. As such, their preparation can take advantage of high geometric surface areas and disregard biomechanical strength. The elution of gentamicin and vancomycin in humans was studied by taking drainage fluid from hips treated with beads or spacers and using polarization immunoassays to determine concentrations. Peak concentrations were significantly higher with beads compared with spacers and were followed for 1 to 2 weeks. There was considerable interconstruct variability, although patients with cement beads consistently produced hip fluid with higher concentrations of antibiotics.


In another study comparing cement beads to fabricated articulating hip spacers, cement beads were the most effective way to enhance antibiotic elution. Of note, this enhancement in elution profile provided by cement beads nearly eliminated the elution differences between Simplex and Palacos. Therefore, (1) Simplex or Palacos cement formulations are likely equivalent for cement bead delivery and (2) it is important to keep in mind the amount of surface area available for drug release when considering the total antibiotic delivery construct.


PMMA Spacers Versus Beads


Antibiotics


The Hip and Knee Section, Treatment, Antimicrobials Proceedings of International Consensus on Orthopedic Infections states: “Antimicrobial therapy should be individualized and based on the sensitivity profile of the microorganism, patient tolerance, and drug side-effect


Jun 18, 2022 | Posted by in ORTHOPEDIC | Comments Off on Antibiotics and Cement
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