Treatment of PJI. Andrej Trampuz Charité University Medicine Berlin Germany

Transcription

1 Treatment of PJI Andrej Trampuz Charité University Medicine Berlin Germany

2 Implants improved life quality

3

4 Treatment

5 Treatment concept To achieve high treatment success, a concerted surgical and antimicrobial concept is needed Cure rate >90%

6 Treatment algorithm Acute PJI Chronic PJI Long-term suppressive antibiotic therapy, permanent arthrodesis/girdlestone - Good bone/soft tissue? - Stable prosthesis? - No DTT (if known)? No Prosthesis exchange Eradication of infection not possible Yes - DTT (if known)? - Bad bone/soft tissue? - Fistula? - Multiple revisions? Yes No Débridement & retention, exchange of mobile parts One-stage exchange Two-stage exchange Three-stage exchange DTT = difficult-to-treat infections caused by pathogens resistant to biofilm-active antimicrobials - Rifampin-resistant staphylococci - Ciprofloxacin-resistant gram-negative bacteria - Fungi (Candida) - DTT-organism? - Bad bone/soft tissue? Short interval (2-3 weeks) No Unsatisfactory course? Yes Long interval (6-8 weeks)

7 Acute infection

8 Prolonged discharge: early postoperative PJI? C-reactive protein (CRP) should decrease after surgery! Exclude other reasons of prolonged discharge (coagulopathy, hematoma, albumin deficiency) revision surgery if prolonged discharge (>7-10 days)

9 Acute pain & fever, 10 y after implantation

10 Bacterial count (log) The solution to pollution is dilution Systemic antibiotic Resistant strains No surgery Insufficient debridement, Sufficient debridement, change of mobile parts Time

11 Antibiotics without surgery Cure rate 8% Cure rate 9% Johnson et al. J Bone Joint Surg Br 1986; Bengtson et al. Acta Orhop Scand 1991

12 Always (!): Change of mobile parts Acute hip and knee infection Debridement & retention Intervention Not changing mobile parts Clinical success 4/52 (7%) Changing of mobile parts 50/55 (91%)

13 Zimmerli W et al. N Engl J Med 2004:351:

14 2004

15 Chronic infection

16 78-y-o female Primary hip prosthesis 4 months ago Since implantation pain, walking distance now 20 m CRP normal, no loosening on x-ray

17 Aspiration 4 months after implantation High leukocyte count in joint aspirate (59,000/µl)

18 Delayed (low-grade) infection Joint aspiration: Culture: Staphylococcus epidermidis Cell count: /µl leukocytes, 90% PMN CRP normal, no prosthesis loosening Prosthesis exchange: 1-stage exchange OR 2-stage exchange with short interval (2 weeks)

19 Treatment algorithm: chronic infection Chronic PJI Prosthesis exchange - DTT (if known)? - Bad bone/soft tissue? - Fistula? - Multiple revisions? Yes No One-stage exchange Two-stage exchange Three-stage exchange DTT = difficult-to-treat infections caused by pathogens resistant to biofilm-active antimicrobials - Rifampin-resistant staphylococci - Ciprofloxacin-resistant gram-negative bacteria - Fungi (Candida) - DTT-organism? - Bad bone/soft tissue? Short interval (2-3 weeks) No Unsatisfactory course? Yes Long interval (6-8 weeks)

20 Aim of PJI-algorithm To select the least invasive treatment option depending on the present features with the best functional result without compromising the cure rate!

21 Surgical procedures Type of surgery Intervention Antibiotics (total 12 weeks) Retention of fixed prosthetic components One-stage exchange Two-stage exchange (short interval) Change of mobile parts Explantation & implantation 2 weeks 10 weeks 2 weeks 10 weeks Explantation Implantation 2 we. 1 week 9 weeks Explantation Implantation Débridement & biopsies i.v. antibiotics without antibiofilm activity p.o. antibiotics without antibiofilm activity p.o. antibiotics with antibiofilm activity Ex- and reimplantation of prosthesis Two-stage exchange (long interval) Explantation 2 weeks 4 weeks 1 week 5 weeks Implantation Biofilm treatment Three-stage exchange 3 weeks 3 weeks 1 week 5 weeks

22 Surgical procedures Type of surgery Intervention Antibiotics (total 12 weeks) Retention of fixed prosthetic components One-stage exchange Two-stage exchange (short interval) Two-stage exchange (long interval) Three-stage exchange Change of mobile parts Explantation & implantation 2 weeks 10 weeks 2 weeks 10 weeks Explantation Implantation 2 we. 1 week 9 weeks Explantation Implantation 2 weeks 4 weeks 1 week 5 weeks Explantation Implantation 3 weeks 3 weeks 1 week 5 weeks Débridement & biopsies i.v. antibiotics without antibiofilm activity p.o. antibiotics without antibiofilm activity p.o. antibiotics with antibiofilm activity Ex- and reimplantation of prosthesis Osteomyelitis treatment

23 Strategy: long 2 W interval 1 W 9 W (6 weeks) Explantation 2 W Implantation 4 W 1 W 5 W Explantation Spacerwechsel No prosthesis 3 W 3 W Osteomyelitis therapy = Suppression Implantation Prosthesis 1 W 5 W Biofilm-active therapy = Eradication No rifampin during interval! rifampin

24 Surgical procedures No drug holidays before reimplantation Type of surgery Intervention Antibiotics (total 12 weeks) Retention of fixed prosthetic components One-stage exchange Two-stage exchange (short interval) Change of mobile parts Explantation & implantation 2 weeks 10 weeks 2 weeks 10 weeks Explantation Implantation 2 we. 1 week 9 weeks Explantation Implantation Débridement & biopsies i.v. antibiotics without antibiofilm activity p.o. antibiotics without antibiofilm activity p.o. antibiotics with antibiofilm activity Ex- and reimplantation of prosthesis Two-stage exchange (long interval) 2 weeks 4 weeks 1 week 5 weeks Explantation Implantation Three-stage exchange 3 weeks 3 weeks 1 week 5 weeks

25 Fast-track -study: Short vs. long interval in twostage prosthesis exchange Explantation 3 we Implantation Two stage (short interval) 4 weeks i.v. 8 weeks p.o. Explantation Implantation 7 weeks Two stage (long interval) 3 weeks i.v. 4 weeks p.o. 1 week i.v. 4 weeks p.o.

26 Median (days) Interval from explantation until reimplantation (hip & knee PJI) Cure rate >90% Year

27 Treatment concept of PJI: Acute infections (<3 weeks of symptoms) Stable prosthesis Good soft tissue No difficult to treat organism (see below) No Difficult-to-treat organism? Rifampin-R staphylococcus Ciprofloxacin-R Gram- rods Fungi Yes No Yes Debridement and retention One stage Only if good soft tissue or Two stage (short interval) Two stage (long interval) 2 weeks i.v. Explantation Explantation 6 weeks i.v. 10 weeks p.o. Explantation and implantation 2-3 weeks i.v. Implantation 2 weeks No treatment Implantation Debridement Biofilm treatment (with rifampin if applicable) Osteomyelitis treatment (no rifampin)

28 2 stage exchange: removal of all foreign material

29 No drug holidays No need: does not change the further treatment Not sensitive (local antibiotics if spacer in situ) Misleading (if false positive/contamination) Additional intervention - additional risk of infection Prolonged treatment (longer exposure to antibiotics and spacer, longer period of immobility) Holidays for patient = holidays for bacteria implantation of a new prosthesis when bacteria are recovered

30 Antibiotics

31 Properties of antibiotics Bactericidal activity Good oral bioavailability Knochenpenetration Good bone Activity against biofilms

32 Bactericidal activity Bacteriostatic Bactericidal Tigecycline TETRACYCLINE OXAZOLIDINONE Linezolid LIPOGLYCOPEPTIDE Telavancin GLYCOPEPTIDE Dalbavancin QUINOLONES Moxifloxacin BETA-LACTAMS Ceftaroline Daptomycin LIPOPEPTIDE OTHER Azithromycin Clindamycin Minocycline Doxycycline Fusidic acid Oxytetracycline Teicoplanin Vancomycin Levofloxacin Ciprofloxacin Nalidixic acid Cefazolin Oxacillin Ampicillin Co-amoxiclav Amoxicillin Streptomycin Flucloxacillin Nafcillin Methicillin Fosfomycin AMINOGLYCOSIDE Amikacin Cephaloridine Rifampin Gentamicin OTHER Penicillin Rolinson GN. Int J Antimicrob Agents 2007;29:3 8

33 How much ends up in the bone? Drug Oral bioavailability Bone penetration Ampicillin/Sulbactam 50% 7% Cefuroxim, cefadroxil 50% 12% Levofloxacin 100% 77% Rifampin 80% 51% Cotrimoxazole 85% 55% Clindamycin 90% 45% Linezolid 100% 85% Sanford Guide to Antimicrobial Therapy nd ed. Lorian. Antibiotics in Laboratory Medicine. 5 th ed.

34 Antibiotics with biofilm-activity Staphylococci: rifampin (in combination) Gram-negative rods: ciprofloxacin Streptococci: penicillin G (amoxicillin p.o.) Enterococci: ampicillin + gentamicin

35 Foreign body infection (FBI) model in guinea pigs Subcutaneous implantation of 4 Teflon cages Infection of cages with different inocula Systemic treatment of infection Aspiration of cage-fluid (planctonic bacteria?) Removal of cages after 5 days and sonication of cages Zimmerli W et al. J Clin Invest 1984;73:

36 Staphylococcal PJI El Helou et al. EJCMID 2010

37 Targeted therapy

38 Empiric treatment No specific exposure: Ampicillin/Sulbactam Fistula, VAC, multiple revisions etc: Piperacillin/Tazobactam Several previous interventions, MRSA-carrier: normal renal function (egfr > 60ml/min): add Vancomycin

39 Switch to oral treatment after surgery When CRP is nearly normalized... wound is closed and dry... organism and its susceptibility is known usually after 2 weeks

40 Rifampin precious but delicate

41 Rifampin Check interactions (CYP450-induction; anticoagulants, antiepileptics, antihypertensive agents, immunmodulators etc) Monitor liver enzymes (toxic hepatitis) Inform patient about red coloration of body fluids (urine, tears)

42 Rifampin: Quick emergence of resistance Do not use: Before surgery In the interval before re-implantation of prosthesis In open wounds As single antibiotic (monotherapy)

43 Therapy during interval: suppression Aim: suppression of the infection (no eradication) used substances: Organism Staphylococci Streptococci Enterococci Anaerobes Gram negative organisms substance Cotrimoxazol, Doxycyclin, Clindamycin Amoxicillin, Clindamycin, Levofloxacin Amoxicillin, (Linezolid) Clindamycin, Amoxicillin, Metronidazole Ciprofloxacin, Cotrimoxazol Seamless intake until implantation (no

44 Suppression with antibiotic cycling Longterm antibiotic therapy is splitted in treatment phases with different antibiotics instead of a single drug Changement of substance every 2-4 weeks 4 weeks cotrimoxazol Indications: No anti-biofilm-active agent available Intolerance of antibiotics/side effects 4 weeks drug holidays 4 weeks doxycyclin Benefits: 4 weeks Bacteria are getting confused prevention clindamycin of emergence of resistance Antibiotic tolerance is better, adverse effects are less

45 Warum Fosfomycin? Anforderung an ein Antibiotikum zur Therapie von Periprothetischen Infektionen (PPI) adäquate Penetration in Haut/Weichteil, Knochen und Biofilm Konzentrationsprofil nach Gabe von 100 mg/kg Fosfomycin Nach 3 h Knochenspiegel = Serum- /Weichgewebespiegel Fosfomycin Vancomycin Schintler 2009

46 Prosthetic Joint Infection Outcome with Fosfomycin The PROOF-study Andrej Trampuz, MD Head of Septic Surgery Unit Center for Musculoskeletal Surgery Charité University Medicine Berlin

47 Allergy Drug fever Toxic hepatitis Toxic nephritis Electrolyte imbalance Adverse effects Psychologic disturbances Myelosuppression C. difficile infection Diarrhea Eosinophilic pneumonia Achilles tendinopathy

48 Monitoring und dose adjustment Monitoring Through level: Vancomycin 2x/week Dose adjustment Kidney function (egfr <60 or 50ml/min) Blood count, creatinin, electrolytes 1x/week Age: reduce dose in patients >75 Jahre Liver enzymes (Rifampin) every 2-4 weeks Weight (>100kg and <40kg)

49 Pathogenesis

50 Pathogenesis of PJI Contiguous spread from adjacent infected tissue Peri- /postinterventional colonisation 5% 20% Hematogenous spread from a distant focus through blood 75% PJIs treated at Charité, 01/ /2018

51 Diagnostic tests Positive test All episodes (n = 106) Increased serum CRP (>10 mg/l) 96/104 (92) Pathological WBC (>10 G/l or <4G/l) 61/104 (59) Elevated synovial fluid leukocyte count 64/64(100) Peri-implant tissue histopathology 86/95 (91) Culture (synovial fluid, tissue or sonication fluid) 99/106 (93) Blood culture 43/70 (61) PJI is easy to diagnose Rakow A, Renz N (own data)

52 Pathogens Highly virulent, i.e. S. aureus, gram-negative bacilli, Streptococcus spp. Rodriguez D, CMI 2010; Uckay I, CMI 2009; Tande AJ, Clin Microbiol Rev 2014 Predominantly monobacterial infections Coagulase-negative staphylococci, 8 Clostridium innocuum, 1 Culture-negative, 1 Gram-negative bacteria, monobacterial 1 polymicrobial 1 culture-negative Enterococcus faecalis, 13 Staphylococcus aureus, 43 Streptococcus spp., 32 Rakow A, Renz N (own data)

53 Primary foci: cohort of 106 episodes 1 (+3?) colon adenoma 1 GI bleeding 2 GI infections Gastrointestinal tract, 7 Others, 3 1 contralat. PJI 1 pneumonia 1 epidural abscess 7 dental treatments 5 dental infections Oral cavity, 12 Unknown, 34 2 manipulations 10 infections Urogenital tract, 12 Skin and soft tissue, 16 Cardiovascular system, 22 9 skin erosion (pedicure, skin disease, chronic ulcers) 7 skin and soft tissue infections 14 endocarditis 5 infected CIED 3 catheter infections Rakow A, Renz N (own data)

54 Investigation of cause Pathogen Source Diagnostics Staphylococci Blood cultures Echocardiography (TEE) Skin examination Streptococci S. oralis/mitis S. agalactiae S. dysgalactiae S. bovis/gallolyticus Enterococci Orthopantomogram (OPTG), dentist, TEE Urinanalysis, imaging abdomen, skin examination, OPTG Colonoscopy Urinanalysis, TEE Enterobacteriaceae Urinanalysis, CT Abdomen Renz N., Chirurg, 2017

55 Reality Bacteremia after tooth brushing and dental extraction Studies not usable (wrong design) Significant bacteremia after dental interventions Prophylaxis reduces bacteremia Clinical practice: association exsists 0 min 1.5min 5min 20min 40min 60min Lockhart PB. Circulation Prospective studies needed

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57 Workshops:

58 Pocket Guide:

59 Consultation service:

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61 Thank you Focus on implant, bone and joint-associated infections: Surgery: New concepts (retention, 1-stage, 2-stage short interval) Diagnosis: Fast innovative methods Antibiotics: Active against biofilms

62 Thank you! Consultation service Pocket Guide Workshops