1

2 Is there any ideal antibiotic or antibiotic-combination to be added in the spacers in the clinical setting? Clinical Infectious Diseases 2012, 55(11) …mainly case series data with only one randomized trial..

3 Son eficaces los espaciadores-AB en recambio dos tiempos Garvin KL, 1995 (29 estudios): EFICACIA: SIN ABCON AB 82%91% (con AB) ¿Características del antibiótico? Activo frente al microorganismo Termoestables (candinas no son termoestables  AB) Hidrosolubles (no hidrosolubles mala liberación) Polvo (líquido no se mezcla con cemento) Escasos efectos secundarios (IR ?  se desconoce) Dextrano (> porosidad, > 25% liberación) Liberación es máxima durante las 1ª 48h (>30 mg/dl) y dismunuye progresivamente (15-30d)

4 Que antibióticos y dosificación Aminoglicósidos (G, T), clinda (macrólidos), vancomicina,.. Dosis Se desconoce dosis idónea (1-10% del cemento) Genta: 1-4g, Vanco: 1,2-4,8g por 40 gr cemento > dósis: < resistencia cemento (< 8g AB por 40 g cemento) Comercial =Manual - Mejor eluciónDósis > elevadas - Liberación conocidaElegir AB - Ventajas trauma Resistente (dificil) - Dósis bajas (1-2g)Peor traumatol - Coste: 3xLiberación ?

5 o In the initial models, the chosen antibiotic was gentamicin [ or tobramycin o Pitto et al. 2005,Pattyn et al. 2011,Wan et al. 2012,Romano et al. 2010]. o Emergence of gentamicin-resistant bacteria (mostly GPC)  the addition of two potentially synergistic antibiotics to bone cement become attractive. Vancomycin - gentamicin Potential synergistic effect Improved elution from bone cement Decreased risk of spacer colonization Decreased risk of gentamicin resistant strains selection o The potential combination of vancomicin and gentamicin in cement spacers has been suggested: Antibioticos solos o combinación?

6 Cultivos 2T y del espaciador Problema: dif coloniz de inf - 1tej + 1 espaciador: probable

7 Rise in aminoglycoside resistance in staphylococci causing PJI?? …GPC susceptibility to aminoglycosides has not been reported routinely in PJI scenarios… Potential contribution of the antibiotic-loaded cement spacers to select resistant mutants in case of infection relapse? … there is no strong evidence to affirm this as a conclusive fact…this risk has brought to attention among scientific community.. Despite the theoretic advantages…are the vanco-genta spacers superior to the genta-spacers in the clinical setting? …whether adding vancomycin to gentamicin-prefabricated antibiotic spacers results in improved infection eradication, less pain, or better function is unknown…

8 J. Arthroplasty 2014 Aug;29 (8) Increase in GPC gentamicin resistant rate? Risk of select resistances after spacer use?

9 Retrospective analysis of 113 consecutive chronic PJI. Group A: 61 cases without previous Gen CS use Group B: 52 cases with previous Gen CS use. Group A: 61 cases without previous Gen CS use Group B: 52 cases with previous Gen CS use. 39 % Gentamicin-R 44 % Tobramicin-R 39 % Gentamicin-R 44 % Tobramicin-R CoN-Staphylococcus (73% of GPC) 41 % CGP Tobramicin-R 32% CGP Gentamicin-R 0 % CGP Vancomycin-R GPC Resist- Rate: Corona PS et al. J. Arthroplasty 2014 Aug;29 (8)...may “potentially impact” the utility of only-aminoglycoside impregnated cement spacers…

10 Previous exposure to gentamicin cement spacer: (…no antibioticos sistémicos) Higher resistance rate among the relapsed cases group  49.2% vs. 19.3 % gentamicin-R (p: 0.0001)  57.4% vs. 25% de CoNS gentamicin-R (p: 0.001) Corona PS et al. J. Arthroplasty 2014 Aug;29 (8)

11 GentamicinVancomycin-Gentamicin 0% vancomycin R 57% >25% G-R after relapse (CoNS) 49%>>19% G-R after relapse 39% Genta-R (CoNS) 32% Genta-R

12 Clin Orthop Relat Res. 2014 Mar;472 (3) Clinical superiority of vanco-genta spacers? Microbiological and Clinical Effectiveness Of Vancomycin Plus Gentamicin Or Gentamicin Loaded Spacers: A Comparative Study T Domingues Frada 1, JC. Martínez-Pastor 2, G Bori 2, E Tornero 2, J M Segur 2, J Bosch 2, S Garcia-Ramiro 2, A Soriano 2 Praga, Mayo 2015

13 Retrospective analysis of 51 consecutive chronic PJI. 51 PJI25 G5 no FU 20 G-CE (43.5%) 26 VG0 no FU 26 VG-CE (56.5%) o Coagulase-negative staphylococci (43%). o Propionibacterium acnes (18%) o Negative culturs (10%) Item Group A: gentamicin Group B: vanco- genta p-val Infection relapse 4/20 (20%)4/26 (15%) 0.73 SAPS (IC95%) 81.67 (25-100)70.63 (25-100) 0.113 SF-12-PSC (IC95%) 29.75 (17.41- 39.71) 31.75 (19.67- 48.21) 0.722 SF-12-MSC (IC95%) 39.82 (15.35- 18.46) 52.59 (28.85- 68.95) 0.131 VAS (IC 95%) 2.41 (0.00-8.00)2.81 (0.00-8.00) 0.821 Final Follow-Up: 12.4 - 64.7 months Overall infection control rate: 83% Corona PS et al. Clin Orthop Relat Res. 2014 Mar;472 (3)

14 Retrospective study (seguimiento 56 meses) Methods January 2003December 2013 146 patients Gentamicin Group (G) n=83 Vanco + Gentamicin Group (V/G) n=63

15 Experts, acollidors i solidaris Results Global rate of infection healing = 75% – At more then 4.5 years of follow up Healing significantly superior for chronic infections (84%) – 84% vs 60% for acute p=0.002 Healing significantly superior with negative cultures on 2nd stage – 81.5% vs 39.1% for positive cultures Rate of negative cultures in second stage was superior in G/V 23.2% vs 6.7% for G, p= 0.001 Healing shows a trend to be superior with V/G spacers (81.9%) – 81.9% vs 69.5% for Gentamicin spacers

16 Results Univariate Analysis FactorPositive Cultures 2nd stage (p) Infection Control (p) Polymicrobian Infection0.014 Chronic vs Acute infection0.002 G spacer vs V/G spacer0.0080.090 No significance for Gender, Diabetes, COPD, Steroid Medication, Renal Failure, Rheumatoid Arthritis, Cirrhosis, ASA score, CRP, BMI, Linezolid intake

17 Results Logistic Regression Model for Positive Cultures on 2nd Stage Factorp-valueOdds RatioCI (Odds; 95%) Polymicrobial Infection0.014.261.44 – 12.64 Use of G spacers0.015.881.60 – 21.74 Logistic Regression Model for infection control at last follow up Factorp-valueOdds RatioCI (Odds; 95%) Chronic Prosthetic Infection0.002 5.432.20 – 13.51 Use of V/G spacers0.0692.360.97 – 5.71

18 Elevadas tasas recidiva: 25-50% con recambio 2T - >ía Azoles prolongados Caso HVH: PTC Candida albicans2T + AnfoB lip(3m)  Voricon F 2T + Esp AnfoB + Anidalafungina (3m) R (3a)

19 Guia diagnóstico-terapéutica infección osteoarticular En el recambio en 2 T se aconseja utilizar un espaciador con antibióticos. (B-II) La dosis de AB local recomendada es de 1,2-4,8g para Vancomicina y 1-4 g para genta y tobramicina (x 40g cemento). (C-III) En espera de una evidencia mejor, es razonable utilizar espaciadores con la combinación vanco-genta. (C-III) En infecciones por multiresistentes pueden utilizarse espaciadores activos frente a éste microorganismo. (C-III) En infecciones por Candida spp, se recomienda utilizar un espaciador de anfo B (C-III)