Tabs or Jabs? Does it make a difference in the treatment of bone and joint infection?

Transcription

1 Tabs or Jabs? Does it make a difference in the treatment of bone and joint infection? The OVIVA teams at 26 NHS trusts Research Ethics Committee Ref No: 13/SC/0016 South Central Oxford REC B No conflicts of interest to declare

2 The Bone Infection Unit, Oxford 7 th Annual Oxford Bone Infection Conference (OBIC) Thursday 22 nd & Friday 23 rd March 2018

3 Background to OVIVA Within NHS per year 250,000 joints & fracture procedures Ø ~6300 post-operative infections Ø ~5000 diabetic foot osteomyelitis Cost 20,000 40,000 per patient Lew DP et al 2004, Zimmerli W et al 2003, Legrand E et al 2001 Berman SJ et al 2001, Matthews PC et al 2007, Tice A et al /2001, Yong C et al

4 ..

5 IV vs PO Study PO / IV N PO (%) Endocarditis Heldman 96 Spontaneous Bacterial Peritonitis Navasa 96 Skin and Soft Tissue Infection (MRSA) Weigelt 05 Community Acquired pneumonia (Paeds) Atkinson 07 Perforated appendix Adibe 08 Febrile neutropenia Gupta 09 S. aureus osteomyelitis Euba 09 Osteomyelitis (Cochrane) Conterno 09 IV (%) p value Cip+Rif / Oxacillin Oflox / Cefotaxime Linezolid / Linezolid Amox / Benpen n/a Co-T / Amp-sulbactam Oflox+Amox / Ceftriax Co-T + Rif / Cloxacillin Various / Various

6 The main finding of this review is the lack of evidence to inform

7 EQUIPOISE No clear evidence that IV antibiotic therapy is superior No clear evidence that PO antibiotic therapy is inferior + Variation in practice à OVIVA a non-inferiority RCT

8 OVIVA Trial design Pragmatic open label, oral vs IV for first 6/52 Antibiotics selected by an infection specialist in all cases Patients had to assume their randomized strategy within 7 days Adjunctive and follow-on oral therapy permitted in both arms Up to 5 days of IV therapy for concomitant and unelated illness if necessary No trial specific samples / investigations / clinics Wide data point margins (@ ~ 6/52, 4/12, 1 yr) Follow up - 1 year Hard end points

9 Inclusion / Exclusion A clinical syndrome comprising any of the following; a) localized pain OR b) localized erythema OR c) temperature >38.0ºC OR d) a discharging sinus or wound AND willing and able to give informed consent AND aged 18 years or above AND the patient has received 7 days or less of intravenous therapy after an appropriate surgical intervention to treat bone or joint infection (regardless of pre-surgical antibiotics) or, if no surgical intervention is required, the patient has received 7 days or less of intravenous therapy after the start of the relevant clinical episode. has a life expectancy > 1 year AND has a bone and joint infection in one of the following categories; a) Native osteomyelitis (i.e., bone infection without metalwork) including haematogenous or contiguous osteomyelitis, and long bone, skull, foot or other foci OR b) Native joint sepsis treated by excision arthroplasty OR c) Prosthetic joint infection treated by debridement and retention, by one stage revision or by excision of the prosthetic joint (with or without planned reimplantation) OR d) Orthopaedic device or bone-graft infection treated by debridement and retention, or by debridement and removal OR e) Spinal infection including discitis, osteomyelitis and/or epidural abscess. Consenting adults Bone, joint or metalware infx Has had < 7 days IV therapy Staphylococcus aureus bacteraemia on presentation or within the last 1 month OR bacterial endocarditis on presentation or within the last month (NB there are no study mandated investigations. Participants are not required to have echocardiograms, blood cultures, or any other investigations to exclude endocarditis in the absence of a clinical indication) OR Any other concomitant infection which, in the opinion of the clinician responsible for the patient, required a prolonged intravenous course of antibiotics (e.g. mediastinal infection or central nervous system infection) OR Mild osteomyelitis, defined as osteomyelitis which, in the opinion of the clinical investigator, would not usually require a 6 week course of intravenous antibiotics OR An infection for which there are no suitable antibiotic choices to permit randomization between the two arms of the trial (for instance, where organisms are only sensitive to intravenous antibiotics, which occurred in <5% of patients during recruitment for our pilot study) OR Previous enrolment in the trial OR Septic shock or systemic features requiring intravenous antibiotics in the opinion of the treating clinician (the patient may be reevaluated if these features resolve) OR The patient is unlikely to comply with trial requirements following randomization (including specific requirement for PO or IV course) in the opinion of the investigator OR There is clinical, histological or microbiological evidence of mycobacterial, fungal, parasitic or viral aetiology OR The patient is receiving an investigational medical product as part of another clinical trial. Needs IVs for other reasons (e.g. Staph bacteraemia, IE, severe sepsis) No oral option Wouldn t normally get 6/52 abx

10 Typical cases Single stage, 1 st stage or DAIR for PJI Long bone osteomyelitis Infected orthopaedic metalware Discitis/spinal osteomyelitis Diabetic foot osteomyelitis i.e. ~ any 6 weeker

11 End points Primary definite treatment failure* Clinical, bacteriological, histological criteria Secondary SAEs (incl. all cause mortality) Line complications C. difficle diarrhoea Probable or possible treatment failure* Early exit from randomised strategy Resource utilisation PROMs (EQ-5D, Oxford hip and knee scores) * All definite, probable and possible treatment failures were reviewed by the EPC using redacted notes

12 Participating centres Birmingham Heartlands Blackpool Brighton and Sussex Bristol Royal Infirmary Cambridge Gartnavel General Guys and St Thomas Hospitals Hull Royal Infirmary Kings Lynn Leeds Teaching Hospitals Maidstone Medway Maritime, Kent Newcastle Norfolk and Norwich Northampton Northumbria North West London North Staffordshire Oxford Royal Cornwall, Truro Edinburgh Royal Free + RNOH, London Royal Hallamshire, Sheffield Liverpool University Hospital University Hospital, North Staffs Tayside, Dundee Tunbridge Wells University College Hospital, London Wittington

13 Milestones Award start: 04/02/2013 Recruitment start: 01/03/2013 Planned recruitment end: 31/10/2015 Planned follow-up end: 31/10/2016 Analysis & write up: Feb 2017

14 OVIVA trial profile

15 ITT 1054 mitt 1015 PP 909

16 Presentation IV PO Total (N = 527) Surgical procedure IV (N = 527) PO (N = 1054) Total Localised pain* 397 (75.33%) (N = 527) 403 (76.47%) 800 (75.90%) (N = 527) (N = 1054) Chronic Localised Site of infection 153 IV 226 (29.03%) (42.88%) 169 PO 207 (32.07%) (39.28%) 322 Total 433 (30.55%) (41.08%) osteomyelitis erythema* (N = 527) (N = 527) (N = 1054) debrided, Spinal Temperature Lower infection* limb no site > of IV (7.02%) (11.76%) PO (6.64%) (11.76%) Total (6.83%) (11.76%) current Upper 38.0 infection C* limb implant or 43 (N(8.16%) = 436) 59 (N(11.20%) = 419) 102 (N = (9.68%) 855) device* infection* Discharging sinus/ 296 (56.17%) 285 (54.08%) 581 (55.12%) Hip* Operative findings 110 IV (25.23%) 104 PO (24.82%) 214 Total (25.03%) Chronic Lower wound* 25 (4.74%) 29 (5.50%) 54 (5.12%) Knee* limb (N = (30.50%) (82.73%) 527) (N = (27.45%) (79.51%) 527) (N = (29.01%) (81.12%) 1054) osteomyelitis infection* as Foot* Draining Organism sinus 89 IV 177 (20.41%) (33.59%) 86 PO 142(26.94%) (20.53%) 175 Total 319 (20.47%) (30.27%) above, Other identified area but not Other arising area from of of bone/ (N(2.28%) = (25.23%) 500) (N(2.66%) = (24.82%) 503) (N(2.47%) = (25.03%) 1003) debrided* infection* Staph. lower prosthesis* Histology/Micro limb aureus IV 196 (39.20%) PO 182 (36.18%) Total 378 (37.69%) Implant diagnostics present* infection* or device 124 (23.53%) Frank pus adjacent 179 (N = (33.97%) 527) 123 (23.34%) 247 (23.43%) 186(35.29%) (N = 527) 365 (N = (34.63%) 1054) present Coagulase and to bone/ 137 (27.40%) 135 (26.84%) 272 (27.12%) Deep Antibiotic tissue IV PO Total retained negative (i.e. histology prosthesis* cement/ beads result* (N = 527) (N = 527) (N = 1054) 'DAIR')* Staphylococcus used Infected 266 (50.47%) 277 (52.56%) 543 (51.52%) Removal present* of 89 (16.89%) 78 (14.80%) 167 (15.84%) Local antibiotic IV PO Total orthopaedic Equivocal Streptococcus device 13 (2.47%) 17 (3.23%) 30 (2.85%) agents No (N(14.40%) = (68.31%) 165) (66.03%) (N(14.51%) = 178) (N = (14.46%) (67.17%) 343) for Uninfected species infection* 31 (5.88%) 32 (6.07%) 63 (5.98%) Comorbidities present* Prosthetic not Cement Gentamicin IV 86 done Pseudomonas joint (52.12%) 28 (12.90%) (40.23%) (24.48%) PO 99 (5.60%) (20.68%) (55.62%) Total (12.71%) (37.38%) (4.57%) (53.94%) 51 (5.08%) (12.81%) (38.80%) (22.58%) Vancomycin (N=527) 29 (17.58%) 31 (N (17.42%) = 527) 60 (N (17.49%) = 1054) implant species missing*** Beads present* removed* 536 (0.95%) (6.83%) 469 (0.76%) (13.09%) 9105 (0.85%) (9.96%) Diabetes* Diagnostic Tobramycin IV (3.03%) (20.30%) PO (18.60%) (6.74%) Total (4.96%) (19.45%) Prosthetic Other Missing Gram joint (N(0.38%) (8.92%) = (16.80%) 527) (N(0.19%) (8.16%) = (16.70%) 527) (0.28%) (8.54%) Renal certainty Other** failure* at (2.09%) (20.61%) (2.09%) (16.85%) (N(2.09%) (18.66%) = (16.75%) 1054) implant, Deep negative tissue 1-stage Ischaemic baseline Missing*** heart (8.16%) (6.67%) 45 6 (3.37%) (8.54%) (8.35%) (4.96%) revision* microbiology disease* organism(s) Definite 478 (90.70%) 476(90.32%) 954 (90.51%) Baseline Summaries Evenly matched

17 Proportion of participants on IV antibiotics (to day 60)

18 Time to permanent discontinuation of antibiotics

19 Forest plot of risk differences (90% CI) for definitive treatment failure (PO vs. IV) ITT IV ( 527) PO (527) Rx failure 74 (14.0%) 67 (12.7%) mitt IV (506) PO ( 509) Rx failure 74 (14.6%) 67 (13.2%) PP IV (443) PO (466) Rx failure 69 (15.58%) 61 (13.09%) (Sensitivity analysis for missing data: Risk difference (PO-IV) = 2.09% and 90% CI: (-1.54, 5.71))

20 Time to treatment failure by randomised treatment strategy

21 Sub-group analyses Five planned and three post-hoc Reported as odds ratios rather than risk differences None were sufficiently powered to provide definitive answer for any subgroup e.g..

22 Odds ratios for treatment failure by surgical procedure Subgroup OR 95% CI N in each group OM debrided (no implant) OM not debrided (no implant) 0.93 (0.45, 1.94) (0.08, 1.41) 76 DAIR 1.20 (0.61, 2.34) 237 Removal of implant 0.65 (0.34, 1.23) stage revision 2.16 (0.58, 8.00) 87

23 Odds ratios for treatment failure by infecting pathogen (PO/IV) Subgroup OR 95% CI N in each subgroup S. aureus 0.89 (0.49, 1.59) 370 Pseudomonas n/a n/a 32 Other GNR 1.13 (0.43, 2.97) 116 Strep. species 0.54 (0.19, 1.55) 81 CNS 0.56 (0.24, 1.32) 189 None identified 1.91 (0.77, 4.75) 227

24 Serious adverse events (excluding line complications and C.diff) Intravenous arm (IV) (N = 527) Oral arm (PO) (N = 527) Total (N = 1054) Number of (220 SAEs) (224 SAEs) SAEs reported (72.30%) 389 (73.81%) 770 (73.06%) (20.68%) 89 (16.89%) 198 (18.79%) 2 20 (3.80%) 29 (5.50%) 49 (4.65%) 3 9 (1.71%) 7 (1.33%) 16 (1.52%) 4 4 (0.76%) 10 (1.90%) 14 (1.33%) 5 1 (0.19%) 2 (0.38%) 3 (0.28%) 6 2 (0.38%) 1 (0.19%) 3 (0.28%) 11 1 (0.19%) 0 (0.00%) 1 (0.09%)

25 Line complications Intravenous arm (IV) (N = 49) Oral arm (PO) (N = 5) Total (N = 54) Mechanical failure 24 (48.98%) 3 (60.00%) 27 (50.00%) Thrombophlebitis/ thrombosis 13 (26.53%) 1 (20.00%) 14 (25.93%) Infection 12 (24.49%) 1 (20.00%) 13 (24.07%) C. difficile diarrhoea IV Antibiotic (N=527) PO Antibiotic (N=527) Total (N=1054) C difficile diarrhea 9 (1.7%) 5 (1.0%) 14 (1.3%)

26 EQ-5D-3L Index over time by treatment arm Mobility Self care Usual activities Pain/discomfort Anxiety/depression VAS Health status

27 Intravenous arm (IV) Oral arm (PO) Total (N = 508) (N = 508) (N = 1016) Median length of stay (IQR ; range) (11, 21),(1, 183) (8, 20),(1, 177) (9, 21),(1, 183)

28 Cost effectiveness planes Cheaper Higher QALYs

29 Cost effectiveness results Outcomes Total non-surgical treatment costs to one year Total QALYs IV PO Mean (SE) Mean (SE) 13,274 ( 446) 10,534 ( 453) (0.013) (0.015) Incremental costs 2,740 ( 638) Incremental QALYs (0.020) Incremental cost-effectiveness ratio Dominant

30 Limitations Open label blinded end point committee Heterogeneity of participants randomised Follow-up to one year pragmatic

31 PO is non-inferior to IV antibiotic therapy in the treatment of bone and joint infection. Good for the health economy Estimated cost saving to the NHS of > 30M Estimated US savings PJI hip and knee >$140M

32 PO is non-inferior to IV antibiotic therapy in the treatment of bone and joint infection. Good for the health economy Estimated cost saving to the NHS of > 30M Estimated cost savings in the US for PJI hip and knee of >$140M Great for practice Reduced risks associated with IV lines Antimicrobial stewardship

33 PO is non-inferior to IV antibiotic therapy in the treatment of bone and joint infection. Good for the health economy Estimated cost saving to the NHS of > 30M Estimated cost savings in the US for PJI hip and knee of >$140M Great for practice Reduced risks associated with IV lines Antimicrobial stewardship Fantastic for patients Early discharge from hospital Convenience, independence and autonomy

34 Thanks to all patients, sites, staff, OPAT teams and the NIHR

35 Actual IV antibiotics used Randomized to IV antibiotics (N = 521) Randomized to PO antibiotic (N = 523) Total (N = 1044) Glycopeptides 214 (41.1%) 22 (4.2%) 236 (22.6%) Penicillins 38 (7.3%) 11 (2.1%) 49 (4.7%) Cephalosporins 173 (33.2%) 8 (1.5%) 181 (17.3%) Carbapenems 41 (7.9%) 5 (1.0%) 46 (4.4%) Other single IV antibiotic 35 (6.7%) 2 (0.4%) 37 (3.5%) Combination IV antibiotics 35 (6.7%) 6 (1.1%) 41 (3.9%)

36 Actual PO antibiotics used Randomized to IV antibiotics (N = 521) Randomized to PO antibiotic (N = 523) Total (N = 1044) Penicillins 8 (1.5%) 83 (15.9%) 91 (8.7%) Quinolones 33 (6.3%) 191 (36.5%) 224 (21.5%) Tetracyclines 4 (0.8%) 57 (10.9%) 61 (5.8%) Macrolides / Lincosamide 10 (1.9%) 68 (13.0%) 78 (7.5%) Other single PO antibiotic 10 (1.9%) 54 (10.3%) 64 (6.1%) Combination PO antibiotics 13 (2.5%) 87 (16.6%) 100 (9.6%)

37 Early exit from randomised strategy Intravenous arm (IV) Oral arm (PO) Total (N = 99) (N = 67) (N = 166) Intolerance 26 (26.26%) 23 (34.33%) 49 (29.52%) Patient preference 19 (19.19%) 5 (7.46%) 24 (14.46%) Difficulties with IV access or administration 41 (41.41%) 0 (0.00%) 41 (24.70%) Intercurrent illness 2 (2.02%) 8 (11.94%) 10 (6.02%) Due to possible or probable recurrence 1 (1.01%) 15 (22.39%) 16 (9.64%) Good clinical response 1 (1.01%) 0 (0.00%) 1 (0.60%) Other 9 (9.09%) 15 (22.39%) 24 (14.46%) Reason not available 0 (0.00%) 1 (1.49%) 1 (0.60%)

38 Self reported adherence at 14 days IV arm (N = 72) PO arm (N = 303) Total (N = 375) Failure rates for PO (N=289) High adherence Medium adherence Low adherence 49 (68.06%) 207 (68.32%) 256 (68.27%) 16 (7.80%) 20 (27.78%) 71 (23.43%) 91 (24.27%) 6 (8.70%) 2 (2.78%) 18 (5.94%) 20 (5.33%) 2 (13.33%)

39 Self reported adherence at 42 days High adherence Medium adherence Low adherence IV arm (N = 80) PO arm (N = 323) Total (N = 403) Failure rates in PO arm (N=303) 54 (67.50%) 166 (51.39%) 220 (54.59%) 20 (12.12%) 21 (26.25%) 117 (36.22%) 138 (34.24%) 9 (7.83%) 3 (3.75%) 25 (7.74%) 28 (6.95%) 3 (13.04%) Missing 2 (2.50%) 15 (4.64%) 17 (4.22%)

40 Odds ratios for treatment failure by retention of metal (post hoc) Subgroup OR 95% CI N in each subgroup No metal retained Metal retained 0.76 (0.47, 1.23) (0.76, 2.49) 324 Metal retained = DAIR and single stage revision No metal = Debridement OM and removal of device or PJ

41 Odds ratios for failure by planned antibiotics (excluding rifampicin) Planned IV therapy Planned PO therapy

42 Odds ratios for treatment failure by planned use of Rifampicin

43 Odds ratios for failure by site (PO/IV)