THE ROLE & RATIONALE OF LOCAL ANTIBIOTICS IN PJI

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1 THE ROLE & RATIONALE OF LOCAL ANTIBIOTICS IN PJI - FOCUS ON BONE CEMENT - DR. C. BERBERICH, PRO-IMPLANT FOUNDATION WORKSHOP PJI, BERLIN, 25. JUNI 2018

2 STRATEGIES TO PREVENT INFECTIONS - INTRAOPERATIVE/SURGICAL MEASURES Skin preparation Draping Changing scalpel blades Bleeding control Dressing Antibiotic prophylaxis systemic local 2

3 CAN WE REALLY RELY ON THE PERIOPERATIVE ANTIBIOTIC PROPHYLAXIS IN ORTHOPAEDIC IMPLANT-SURGERIES?

4 ANTIBIOTICS RELEASED FROM LOCAL CARRIERS PROVIDE A SECOND FRONTLINE OF INFECTION PROPHYLAXIS 4

5 CATHEGORIES OF LOCAL ANTIBIOTIC CARRIERS Temporary Biodegradable Implants Temporary Nondegredable Implants Bone Substitution / Reconstruction Materials Antibiotic Loaded Fleeces PMMA Chains PMMA Spacers PMMA Rods Permanent Nondegredable Implants Bone Cements Bone Substitution Materials PMMA Rods

6 PROF. BUCHHOLZ PIONEERED THE USE OF BONE CEMENT AS LOCAL ANTIBIOTIC CARRIER Letter from Buchholz 1969 to Heraeus Kulzer & Merck Prof. Buchholz, former head of the Endoclinic Hamburg Sir John Charnley, UK Nothing leaks out of a stone, my dear Buchholz!

Infection Rate (%) DRASTIC REDUCTION OF PJI INCIDENCE RATE OVER THE LAST DECADES 8 7 6 5 4 7,5 Bone Cement w/o AB 4,1 New surgical techniques Better hygiene OR Use of antibiotics (systemic + local)

7 Infection Rate (%) DRASTIC REDUCTION OF PJI INCIDENCE RATE OVER THE LAST DECADES ,5 Bone Cement w/o AB 4,1 New surgical techniques Better hygiene OR Use of antibiotics (systemic + local) Bone Cement (PALACOS) + Gen Prof. Buchholz, former head of the Endoclinic Hamburg 3 2 1,6 1,4 1,5 1, ,6 0,8 0,7 0,4 0, Swedish arthroplasty register data; Philips JE et al. The incidence of deep prosthetic infections in a specialistorthopaedic hospital: a 15-year prospective survey. J Bone Joint Surg (Br) 2006; 88:

8 BONE CEMENT AS CARRIER ALLOWS DELIVERY OF HUGE CONCENTRATIONS OF ANTI-INFECTIVE DRUGS INTO THE BONE & JOINT COMPARTMENT Red man syndrome Side effects with local antibiotics are rare even at high amounts

HUGE INTRA-ARTICULAR CONCENTRATIONS OF ANTIBIOTICS RELEASED FROM BONE CEMENT Conclusions the concentrations of gentamicin found inside isolated gaps within 2 h are

9 HUGE INTRA-ARTICULAR CONCENTRATIONS OF ANTIBIOTICS RELEASED FROM BONE CEMENT Conclusions the concentrations of gentamicin found inside isolated gaps within 2 h are about 1000 times higher than MICs for staphylococci This may be expected to effectively decontaminate the prosthesis related interfacial gap directly after implantation

10 EVEN RESISTANT BACTERIA MAY BE KILLED AT HIGH LOCAL ANTIBIOTIC CONCENTRATIONS MIC wildtype 0,5ug/ml MICs 1500 clinical samples Gentamicin in Staphylococcus Coagulase-negative EUCAST data base 2013 initial antibiotic concentrations at bone cement interface

11 USE OF LOW AND HIGH DOSE ANTIBIOTIC-LOADED BONE CEMENT (ALBC) Use of ALBC Primary arthroplasty Septic revision arthroplasty Routine Prophylaxis Special Prophylaxis & Treatment Low-dose ALBC empirical use of a broadspectrum antibiotic High-dose ALBC targeted use of antibiotic combinations

Insufficient debridement Nonappropriate antibiotics

12 HOW TO PREVENT THE DEVELOPMENT OF RESISTANT BACTERIA ON BONE CEMENT IN SEPTIC REVISIONS? Insufficient debridement Nonappropriate antibiotics Bacterial (re)colonization A priori resistant germs Insufficient antibiotic elution

CFU of S. epidermidis on cement discs - 10 3-10 3-10 7 PALACOS PALACOS R+G COPAL G+C S. epidermidis day 1 S.

13 10 log CFU/cm 2 A HIGH DOSE DOUBLE ANTIBIOTIC-LOADED CEMENT REDUCES GROWTH OF BACTERIA MORE EFFICIENTLY THAN A LOW DOSE CEMENT Colonies on plain Palacos (w(o) Few destroyed colonies on COPAL G+C Inoculum CFU of S. epidermidis on cement discs PALACOS PALACOS R+G COPAL G+C S. epidermidis day 1 S. epidermidis day 7 Source: Ensing et al.. Clin Orthop Rel Res 2008 (466), 1492; Neut et al. J Biomed Mater Res 2005; 165

14 ADVANTAGE OF USING ANTIBIOTIC COMBINATIONS IN BONE CEMENT

15 SYNERGISTIC RELEASE EFFECT OF SOME COMBINATIONS Matrix: Bone Cement with Gentamicin + Clindamycin + Cipro/Levofloxacin + Vancomycin + Colistin (+ Meropenem) Strong synergistic release effect

16 SYNERGISTIC ANTIMICROBIAL EFFECT OF SOME COMBINATIONS Synergism in antimicrobial efficacy of gentamicin & clindamycin Synergism in antimicrobial efficacy of vancomycin & gentamicin gentamicin clindamycin gentamicin + clindamycin Source: Watanakunakorn et al Journal of Antimicrobial Chemotherapy 6, ; Watanakunakorn et al Antimicrobial Agents and Chemotherapy,

PREMIXED ANTIBIOTIC COMBINATIONS IN BONE

17 PREMIXED ANTIBIOTIC COMBINATIONS IN BONE CEMENT COPAL bone cement with gentamicin & clindamycin COPAL bone cement with gentamicin & vancomycin Propioni acnes MRSA Gehrke, T.: Neuer Antibiotikahaltiger Knochenzement. Medizin Forum aktuell. Nr. 64, 1998

NOT ANY ANTIBIOTIC CAN BE USED WITH BONE CEMENT Liquid antibiotics Strong reduction of mechanical strength (fixation cement) Interference with PMMA polymerization Rifampicin (no cement curing)

18 NOT ANY ANTIBIOTIC CAN BE USED WITH BONE CEMENT Liquid antibiotics Strong reduction of mechanical strength (fixation cement) Interference with PMMA polymerization Rifampicin (no cement curing) Thermal instability or fast breakdown Flucloxacillin, Chloramphenicol, Tetracycline, Imipeneme Allergies Cave Penicillins Picknell B et al Antibacterial activity of antibiotics in acrylic bone cement. J Bone Joint Surg Br. 1977; 59:302-7; Bridgens et al. Orthopaedic bone cement: do we know what we are using? J Bone Joint Surg Br 2008; 90:643-7; Webb and Spencer The role of PMMA bone cement in modern orthopaedic surgery. JBJS (Br.); 89-B:

19 NOT ALL ANTIBIOTICS ARE STABLE IN BONE CEMENT OVER TIME Christof Berberich, Ph.D. Heraeus-Medical, Nov. 2016, Version 1.0_en Samara et al. Bone Joint Res 2017;6:

20 To order or download: /27/2018

21 PROBLEMS OF MANUAL ADMIXING OF ANTI-INFECTIVE DRUGS Mechanical stability? Reproducible drug release? Product liability?

22 WHAT IS THE EVIDENCE FOR ADDITIONAL BENEFIT OF LOCAL ANTIBIOTICS IN ARTHROPLASTY? WE MUST ADMIT THAT HARD EVIDENCE DATA FROM RCTS ARE OFTEN LACKING. CURRENT PRACTICE REFLECTS RATHER EXPERT RECOMMENDATIONS AND COHORT/REGISTRY OBSERVATIONS

23 SCANDINAVIAN ARTHROPLASTY REGISTRIES: LESS REVISIONS IF COMBINING SYSTEMIC & LOCAL PROPHYLAXIS Norwegian Hip Registry Finnish Knee Registry 23

24 IMPACT OF ALBC ON RE-REVISION RISK IN KNEE ARTHROPLASTY

25 RETROSPECTIVE ANALYSIS FROM 14 FRENCH CENTRES: THE USE OF ALBC LEADS TO BETTER CLINICAL RESULTS IN SEPTIC REVISION SURGERY % cured infections 14 French teaching centres Follow-up time: 2 years 1-stage w/o ALBC, n=136 1-stage with ALBC, n=838 2-stage w/o ALBC, n=532 2-stage with ALBC, n=

26 A HIGH-DOSE DUAL ANTIBIOTIC CEMENT REDUCES NUMBER OF INFECTIONS IN HIGH RISK PATIENTS RESULTS: PALACOS COPAL Deep SSI after 1 yr 3,5% 1,1%, p=0,041 Number of Staphylococcus infections drastically reduced in in COPAL group

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28 BACKUP

In Vivo and In Vitro Studies of Antibiotic Release from and Bacterial Growth

29 HOW LONG DO PMMA SPACER ELUTE THE ANTIBIOTICS? Explanted Hip Spacers S. epidermidis growth inhibition of explanted spacers Kelm et al. In Vivo and In Vitro Studies of Antibiotic Release from and Bacterial Growth Inhibition by Antibiotic-Impregnated Polymethylmethacrylate Hip Spacers. Antimicrob. Agents Chemother. 2006; 50:

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