Addition of Antibiotics to Cement - Wheeless' Textbook of Orthopaedics

- See: Infection Menu and Wound Management:

- Discussion:

- basic science:
      -
      - references:
             - In vitro characteristics of tobra PMMA beads: compressive strength and leaching.  Kirkpatrick et al. Orthopedics. Vol 8. 1130-1133. 1985.
             - Antibiotic impregnated bone cement in total hip arthroplasty. An in vivo comparison of the elution properties of tobramycin and vancomycin.
              - Long-term elution of antibiotics from bone-cement: an in vivo study using the prosthesis of antibiotic cement (PROSTALAC) system.
              - High concentration and bioactivity of vancomycin and aztreonam eluted from Simplex cement spacers in two-stage revision of infected hip
                       implants: a study of 46 patients at an average follow-up of 107 days.

- complications and safety issues:
- in the report by Springer et al total antiobiotic load of 10.5 g of vanc and 12.5 g of gent was clinically safe, w/ no evidence of acute renal
insufficiency or other systemic side effects;
- in the report by van Raaij et al, authors note a case of renal failure with 2 gm of gent (serum levels of gent were high);
- references:
              - Systemic safety of high-dose antibiotic-loaded cement spacers after resection of an infected total knee arthroplasty.
- Acute renal failure after local gentamicin treatment in an infected total knee arthroplasty.
              - Audiometric thresholds in osteomyelitis patients treated with gentamicin-impregnated methylmethacrylate beads (Septopal).
              - Acute renal failure associated with vancomycin- and tobramycin-laden cement in total hip arthroplasty.

- Addition of Antibiotics to Cement for Treatment of Osteomyelitis: (see OM and post traumatic tibial OM)

    - as noted by Keating et al 1996, bead pouches help reduce the infection rate in open tibia fractures from 16% to 4%;
    - structural support:
- references: Antibiotic Cement-Interlocking Nail for Infected Nonunions and Segmental Bone Defects.
- cement beads for treatment of osteomyelitis:
- after fracture stabilization has been completed, osseous defects may be filled w/ antibiotic-PMMA beads;
- these beads provide local depot administration of antibiotic and maintain space for subsequent bone graft;
        - add 2.4 gm of tobramycin per cement package, and fashion small beads attached to a O silk suture;
- once cement no longer sticks to fingers, roll cement into small spheres and thread over 18 gauge wire or #2 Ethibond;
- counting the beads and adding methylene blue helps ensure that none of the beads will be left behind at removal;
- references:
- Antibiotic bead chains.
- The antibiotic bead pouch technique. The management of severe compound fractures.
- Long-term implantation of gentamicin-polymethylmethacrylate antibiotic beads.
- Gent-impregnated methylmethacrylate beads compared with systemic antibiotic therapy in the treatment of chronic osteomyelitis.
             - Septopal beads and autogenous bone grafting for bone defects in patients with chronic osteomyelitis.
- The use of tobramycin-impregnated polymethylmethacrylate beads in the therapy of deep bone and joint infections.
- Reamed Nailing of Open Tibial Frx: Does Antibiotic Bead Pouch Reduce Deep Infection Rate? J. Orthop. Trauma. 1996. Vol 10. p 298-303.
- In vitro characteristics of tobramycin PMMA beads: compressive strength and leaching. DK Kirkpatrick. Orthopedics. Vol 8. 1130-1133. 1985.
             - Comparison of clinical efficacy and tolerance of gent PMMA beads on surgical wire versus combined and systemic therapy for OM.
             - The treatment of infected nonunions with gentamicin-polymethylmethacrylate antibiotic beads.
             - The role of local antibiotic therapy in the management of compound fractures.

- Technical Considerations for Joint Replacement:
            - StageOne™ Knee Cement Spacer Molds
            - StageOne™ Hip Cement Spacer Molds
            - references:
                    - Successful treatment of total hip and knee infection with articulating antibiotic components: a modified treatment method.

- Protocols for Addition for Antibiotics to Cement:
- in the study by Koo et al., 21 of 22 patients were sucessfully treated with staged revision using 2 g each of vanc, gent, and cefotaxime per 40 g of cement;
- in the study by Masri et al, the authors conclude that at least 3.6 g of tobra and 1 g of vanc per package of bone-cement is recommended in 2-stage exchange
           arthroplasty for infected total hip and knee arthroplasties;
- there was a statistically significant increase in elution of vanc when dose of tobra was increased from at most 2.4 g to at least 3.6 g;
- in the study by Evans et al, the authors used 4 g of vanc and 4.6 g of tobra per 40 gm batch of cement in 54 periprosthetic joint infections;
- at 2 year follow up there were no no renal, vestibular, or hearing changes;
- dosing and biomechanical strength considerations:
- addition more than 4.5 g of powder substantially weakens bone cement;
- approx 8 grams of antibiotic powder per 40 gm of cement is the highest amount that can be added;
- antibiotics added in liquid form dramatically decrease strength characteristics;
- references: Two-stage revision THR for infection with a custom-made, antibiotic-loaded, cement prosthesis as an interim spacer.
- mixing protocol:
- cement liquid and powder is mixed together first, and then antibiotic powder is added;
- this leaves as many large crystals intact as possible to create a more porous mixture to increase antibiotic elution rate;
- antibiotics must be added to the cement in a powered form (which may or may not be available from the pharmacy);
- vacuum-mixing is not used: decreases the porosity of the cement, which also decreases rate of elution of the antibiotics;
- reference:
                    - Practical applications of antibiotic-loaded bone cement for treatment of infected joint replacements.
                    - Volume and surface area study of tobramycin-polymethylmethacrylate beads.
      - palacos cement:
- superior ATB elution characteristics for treating osteomyelitis;
- higher porosity allows for improved elution characteristics but may make it less amenable to modern cementing techniques;
              - when mixing the cement it is important not decrease the porosity of the cement by not using the vacuum pump;
- temporary spacer:
- tobramycin: add 2.4 to 3.6 grams per 40 gm package of cement;
- vancomycin: add 1-4 grams per 40 grams of cement;
- simplex-p bone cement
- loaded w/ antibiotics (0.6 to 2.4 grams of tobramycin & 0.5 to 1.0 gram of vancomycin per forty grams of cement)
- has superior handling characteristics;
- amount of ATB that can be added to Simplex Cement (40 gm/pack);
- cefazolin: 6.0 gm (may be heat labile?)
- tobramycin: 9.6 gm
- vancomycin: 5.0 gm
- based on allowed volume (24 cc ATB / 120 cc cement);

- Characteristics of Individual Antibiotics:
- note that lincomycin, tetracycline, and rifampin should not be added to methylmethacrylate;
- note: the antibiotics must be added to the cement in a powered form (which may or may not be available from the pharmacy);
- in general the addition of antibiotics to cement during arthroplasty will not interfere with mechanical properties if the amount of
           antibiotics is kept less than 2.5 gm per 40 grams;
- gentamicin:
           - in the report by Springer et al total antiobiotic load of 10.5 g of vanc and 12.5 g of gent was clinically safe, w/ no evidence of acute renal
insufficiency or other systemic side effects;
           - elution falls below the mean inhibitory concentration by 6-8 weeks;
- currently the powered form of genatmicin is not available in the US;
- references:
- A comparison of gent polymethylmethacrylate bead implantation to conventional parenteral antibiotic therapy in infected THR and TKR.
                  - Comparison of the clinical efficacy and tolerance of gent PMMA beads on surgical wire versus combined and systemic therapy for osteomyelitis.
- Long-term implantation of gentamicin-polymethylmethacrylate antibiotic beads.
- Audiometric thresholds in osteomyelitis patients treated with gent-impregnated methylmethacrylate beads (Septopal).
- Gent-impregnated polymethylmethacrylate beads compared with systemic antibiotic therapy in the treatment of chronic osteomyelitis.
- The treatment of infected nonunions with gentamicin-polymethylmethacrylate antibiotic beads.
- Reimplantation in infection: elution of gent from cement and beads. EA Salvati et al. CORR. Vol 207. 1986. p 83-93.
- Total hip joint arthroplasty with gent-impregnated cement. C Torholm et al. CORR. Vol 181. 1983. p 99-106.
- The release of gent from PMMA beads: An experimental and pharmacokinetic study.  JBJS. Vol 60-B. 1978. p 270.
                  - A comparison of gent-impregnated PMMA bead implantation to conventional parenteral antibiotic therapy in infected THR and TKR.
    - vancomycin:
- has much slower and more consitent elution characteristics than tobramycin;
- as much as 4 gm of Vancomycin (as well as 4.6 gm of tobramycin) can be used per batch of cement;
- in the study by Evans et al, the authors used 4 g of vanc and 4.6 g of tobra per 40 gm batch of cement in 54 periprosthetic joint infections;
- at 2 year follow up there were no no renal, vestibular, or hearing changes;
- note that the cost for a 1 gm vial is about 40 US dollars;
- in the study by Masri et al, authors conclude that at least 3.6 g of tobra and 1 g of vanc per package of bone-cement is recommended when antibiotic-loaded cement
spacers are used in 2-stage exchange arthroplasty for infected total hip and knee arthroplasties;
- there was a statistically significant increase in elution of vancomycin when dose of tobra was increased from at most 2.4 g to at least 3.6 g;
           - in the report by Springer et al total antiobiotic load of 10.5 g of vanc and 12.5 g of gent was clinically safe, w/ no evidence of acute renal
insufficiency or other systemic side effects;
           - references:
- Use of vancomycin and tobra polymethylmethacrylate impregnated beads in the management of chronic osteomyelitis.
- Elution characteristics of vanco and tobramycin in acrylic bone cement. MJ Penner et al. J. Arthroplasty. Vol 11. p 939-944. 1996.
                  - Antibiotic impregnated bone cement in total hip arthroplasty. An in vivo comparison of the elution properties of tobramycin and vancomycin.
                  - Impregnation of vancomycin, gent, and cefotaxime in a cement spacer for two-stage cementless reconstruction in infected THR.
                  - Elution of vancomycin, daptomycin, and amikacin from acrylic bone cement.
                  - High active local levels of vancomycin without nephrotoxicity released from impacted bone allografts in 20 revision hip arthroplasties.
                  - Vancomycin-supplemented cancellous bone allografts in hip revision surgery.

    - tobramycin:
- has rapid elution of antibiotics which diminishes quickly after 2 weeks;
- of interest, some bacteria will be able to survive on tobra or vanco beads alone, but generally cannot survive when both antibiotics are added to cement mixture;
- the addition of 3.6 gm of powered tobramycin / 40 gm of cement should not raise the serum levels above 3 mg / dl;
- some authors routinely add 4.8 gm per 40 gm cement batch;
- note the cost for a 1.2 gm vial is about 250 US dollars;
- in the study by Evans et al, authors used 4 g of vancomycin and 4.6 g of tobramycin per 40 gm batch of cement in 54 periprosthetic joint infections;
- at 2 year follow up there were no no renal, vestibular, or hearing changes;
- note that the cost for a 1 gm vial is about 40 US dollars;
- in the study by Masri et al, the authors conclude that at least 3.6 g of tobramycin and 1 g of vancomycin per package of
                  bone-cement is recommended when antibiotic-loaded cement spacers are used in 2-stage exchange arthroplasty for infected total hip and TKR;
- there was a statistically significant increase in the elution of vancomycin when dose of tobramycin was increased from at most 2.4 g to at least 3.6 g;
- references:
                  - Antibiotic impregnated bone cement in THR. An in vivo comparison of the elution properties of tobramycin and vancomycin.
- The use of tobramycin-impregnated polymethylmethacrylate beads in the therapy of deep bone and joint infections.
- Effectiveness of bone cement containing tobra. An in vitro suseptibility study of 99 organisms found in infected JA. CP Scott et al. JBJS. Vol 81-B. May 1999. p 440.
    - erythromycin:
- 1 gm of erythromycin per 40 gm packet of cement;
- has good bacterial spectrum, rarely causes allergies, and has good elution from cement;