Early oral switch for antibiotic treatment of infective endocarditis

Transcription

1 AEPEI: Association pour l Etude et la Prévention des Endocardites Infectieuses Early oral switch for antibiotic treatment of infective endocarditis Prof. Pierre Tattevin Infectious Diseases & ICU, INSERM U 835 Pontchaillou Univ Hosp, Rennes, France

2 Highlights (1) Facts Bacterial endocarditis is one of the most difficult-to-treat bacterial disease Experimental models of infective endocarditis (IE) Clinical studies in humans prolonged, high-doses, i.v., bactericidal regimens A few situations have been identified where regimens could be safely stepped down Right-sided staphylococcal endocarditis in IVDU => oral treatment Non-complicated, susceptible streptococci => 2 weeks parenteral combo

3 Highlights (2) Prospects Additional groups of IE patients may be treated less extensively New strategies => use medical progress! Biomarkers may be used as prognostic factor More oral antibacterial agents Progress in therapeutic drug monitoring Imaging (e.g. TEP, to rule out extracardiac complications, or to monitor IE activity during treatment) Randomized clinical trials for IE oral switch in IE patients controlled by initial IV

4 Facts Experimental data Clinical studies

5 Endocarditis rabbit model Pretreatment with warfarin => no vegetation Usual IE model Anticoagulated rabbit => IE, but no vegetation

6 Short treatment effective in experimental IE without vegetations Hook III EW, Sande MA. Infection Immunity 1974

7 Why are vegetations so important for the success of IE treatment regimens? Antibiotics diffusion rather good overall in veget. Subcutaneous fibrin clots model Rabbit endocarditis model Human data (valvular replacement surgery) Equilibration between ATB concentrations in serum and vegetations is rapid and almost complete, with similar PK parameters for most drugs used for EI treatment Daschner FD, Frank U. J Antimicrob Chemother 1987 Crémieux AC, Carbon C. Antimicrob Agents Chemother 1992

8 Why do we need to treat IE so long? Untreated, experimental strepto IE (rabbits) Vegetations Day 3 => day 14 Incubation in glucose broth with 3 H-alanine => Deep bacterial colonies have reduced metabolic activity Durack D, Beeson P. Br J Exp Path 1972

9 Reduced metabolic activity of bacteria in vegetations Experimental strepto IE (rabbits) Such foci are likely to be in a resting phase prior to Vegetations Day 3 => day 14 death... If so, they would be unaffected by antibiotics Incubation in glucose broth with 3 H-alanine and could cause relapse after therapy. The fact that this healing process requires 2 or more weeks explains why successful antibiotic therapy must be prolonged over the same period to prevent relapse. => Deep bacterial colonies have reduced metabolic activity Durack D, Beeson P. Br J Exp Path 1972

10 Alteration of bacteria within vegetations Untreated, experimental strepto IE (rabbits) Vegetations day 7 => day 18 Transmission electron microscopy Morphological anormalities after day 10 + excess of exopolysaccharide Trehel C et al. Microbial Pathogenesis 1988

11 Alteration of bacteria within vegetations Day 7 Day 18

12 Principles of antibacterial treatment for IE Vegetations: In vitro & experimental studies High inoculum ( CFU/g, from day 1 in rabbits) Poor local immunity (polynuclear leucocytes scant ) Highly effective bactericidal regimen required initially Then, main issue = altered bacteria metabolism Prolonged half life, limited susceptibility to antibiotics Appropriate duration of treatment (long enough) => avoid relapses! Durack D et al. Br J Exp Path 1973 Scheld WM. J Antimicrob Chemother 1987

13 Facts Experimental data Clinical studies

14 The early strepto IE trials Penicillin low dose Verhagen DWM et al. J Antimicrob Chemother 2006

15 The early strepto IE trials Penicillin low dose Verhagen DWM et al. J Antimicrob Chemother 2006

16 Strepto IE trials, Shorter treatment schedules (2 weeks) Verhagen DWM et al. J Antimicrob Chemother 2006

17 Strepto IE trials, Shorter treatment schedules (2 weeks) Verhagen DWM et al. J Antimicrob Chemother 2006

18 Strepto IE trials, Shorter treatment schedules (2 weeks) Verhagen DWM et al. J Antimicrob Chemother 2006

19 How long does it take to sterilize infected cardiac valves in humans? Retrospective study of all IE patients who underwent valve surgery Auckland New Zealand, , n=506 Analyzed the proportion of culture-positive valves, as a function of the duration of IE treatment received prior to surgery Morris AJ et al. Clin Infect Dis 2003

20 How long does it take to sterilize an infected valve in humans? Retrospective study of all patients who underwent valve surgery with the diagnosis of IE Auckland New Zealand, , n=506 Morris AJ et al. Clin Infect Dis 2003

21 How long does it take to sterilize an infected valve in humans? Retrospective study of all patients who underwent valve surgery with the diagnosis of IE Auckland New Zealand, , n=506 Morris AJ et al. Clin Infect Dis 2003

22 How long does it take to sterilize an infected valve in humans? Retrospective study of all patients who underwent valve surgery with the diagnosis of IE Auckland New Zealand, , n=506 Morris AJ et al. Clin Infect Dis 2003

23 How long does it take to sterilize an infected valve in humans? Retrospective study of all patients who underwent valve surgery with the diagnosis of IE Auckland New Zealand, , n=506 Morris AJ et al. Clin Infect Dis 2003

24 How long does it take to sterilize an infected valve in humans? Retrospective study of all patients who underwent valve surgery with the diagnosis of IE Auckland New Zealand, , n=506 Morris AJ et al. Clin Infect Dis 2003

25 Oral treatment for uncomplicated rightsided staphylococcal IE in IVDU San Francisco, SFGH, Observational study, 10 patients, 100% cure Rifampin, 300 mg b.i.d. PO x 28 days Ciprofloxacin, 300 mg b.i.d. IV x 7 days, then 750 mg PO b.i.d. X 21 days Baltimore, Randomized, open-label, multicentric study 29 patients (69% HIV+), 90% cure (91% in IV group) Rifampin, 300 mg b.i.d. PO x 28 days Ciprofloxacin, 750 mg PO b.i.d. X 28 days Dworkin RJ et al. Lancet 1989 Heldman AW et al. Am J Med 1996

26 Could we use biomarkers for oral switch or shorter treatment in IE? Multi-center, prospective, observational ( ) Left-sided, native valve, definite IE Measurements of CRP baseline 3 times a week until end of treatment What is the value of serial CRP as a predictor of outcome? * Poor outcome defined as serious infectious complications, or death, between diagnosis and M3 Verhagen D. et al. Arch Intern Med 2008

27 Could we use biomarkers for oral switch or shorter treatment in IE? If D7 CRP > 122 mg/l, OR for poor outcome = 10.3 D7 CRP as a marker of Baseline & D7 CRP predict outcome patients with IE who may be If 75% decline => 19% risk of poor outcome cured with less drugs? If no decline => 52% risk of poor outcome Verhagen D. et al. Arch Intern Med 2008

28 Summary Current recommendations for duration of medical treatment for IE are accurate However, limited evidence that high doses i.v. bactericidal regimen must be maintained throughout We may allow simplified regimen for most patients with IE => new concept induction/maintenance

29 Words of caution (1) - Be sure there is no difficult-to-treat extracardiac infected site (vertebral osteomyelitis, brain abscess, etc..) - Some bacteria may have no mercy (e.g. Enterococcus sp., non-susceptible or nutritionally-variant streptococci, MRSA) - Most clinical studies on oral treatment for IE have been performed with no echocardiography criteria, and limited sample size - When simplification implies broader spectrum, consider risk/benefit ratio (e.g. ceftriaxone for multi-susceptible strepto; fluoroquinolones for MSSA )

30 Words of caution (2) - A few case reports of rapid emergence of fluoroquinolone resistance on IE treatment (including one case of acquired co-resistance to rifampin/ciprofloxacin) Tebas P et al. J Infect Dis 1991

31 The real life (1) IE patients, well controlled with 2 weeks i.v. 29% of IE patients (19/66) underwent oral switch in a recent observational study Not supported by any clinical trial in most cases left-sided IE prosthetic valve IE MRSA Regimens for oral switch were based on susceptibility profile, PK/PD concept, etc.. => 100% success! Demonchy E. et al. Med Mal Inf 2011

32 The real life (2) 35 cases of suspected S. aureus IE Inclusion criteria: 3 blood cultures + murmur Oral swith after a median of 16 days i.v., to cloxacillin or flucloxacillin, 4.5 g/d (n=30) clindamycin (n=4), penicillin V (n=1) mean duration oral = 26 days => 100% success! Parker RH, Fossieck BE Jr. Ann Intern Med 1980

33 Prospects Randomized, non-inferiority clinical trials

34 The POET study Partial Oral treatment for EndocardiTis Objectives To evaluate safety & efficacy of partial oral treatment for leftsided IE, compared with full-length parenteral treatment Design Multicenter, nationwide (Denmark) Randomized 1:1 Open-label, non-inferiority study Funding: Danish Heart Foundation + participating centers Iversen K et al. Am Heart J 2013

35 The POET study Iversen K et al. Am Heart J 2013

36 The POET study Iversen K et al. Am Heart J 2013

37 The POET study And at last 10 days of Iversen ATB K treatment et al. Am Heart remain J 2013

38 The POET study Methods Guidelines for the choice of oral switch (combinations) Plasma PK after randomization Day 1: 0.5, 1, 2 & 4 hours post-administration Day 5: Trough Failures will be investigated in depth (resistance, etc.) Primary endpoint: composite, M6 post discharge Mortality Unplanned surgery Relapse Embolic events Iversen K et al. Am Heart J 2013

39 The POET study Sample size Based on literature & experience, primary endpoint (failure) expected in 5-10% of patients randomized Power 90%, delta 10%, 1-sided CI 97.5%, LTFU 5% Target = 400 patients to be enrolled Update Trial ongoing (enrolment start, July 2011) 300 patients enrolled => study extended (enrolment till 2016) No intermediate analysis planned So far, so good! Henning Bundgaard, personal communication, June. 2015

40 The POET study Potential limitations Heterogeneity (pathogens, native & prosthetic valves, different treatment regimens) The study aims to address a treatment strategy rather than any specific treatment. A study with sufficient statistical power to investigate all subgroups, pathogens, and treatment regimens would require considerably more patients Iversen K et al. Am Heart J 2013 The low rate of antibacterial resistance in Denmark

41 So The RODEO study Relais Oral Dans les Endocardites à staphylocoques multi-sensibles Objectives To evaluate safety & efficacy of partial oral treatment for leftsided multi-susceptible staphylococcal IE, compared with fulllength parenteral treatment Design Multicenter, nationwide (France) Randomized 1:1, open-label Funding (550 k ): French Ministry of Health (PHRC) L. Bernard, C. Pulcini, P. Tattevin

42 The RODEO study Inclusion criteria Native or prosthetic valve Coagulase negative or S. aureus Susceptible to meticillin, fluoroquinolones and rifampin > 14 days of recommended parenteral treatment received and > 14 days of antistaphylococcal treatment remain Stratified on valvular replacement for current IE Stable T < 38 C (100.3 F) for > 2 days Blood cultures sterile for > 5 days No additional surgery planned Able to take oral drugs

43 The RODEO study Methods Experimental arm (oral) levofloxacin (500 or 750 mg o.d.) + rifampin (600 or 900 mg o.d.) Control arm: European guidelines (2009) Primary endpoint: composite, M3 post treatment Mortality Unplanned surgery Relapse => Adjudicated by an independent committee, blinded to randomization arm

44 The RODEO study Sample size Primary endpoint expected in 10% of patients randomized Power 80%, delta 10%, 1-sided CI 97.5%, LTFU 10% Target = to enrol 324 patients Update Not selected when first submitted (2013, feasibility issues) Re-submitted with additional sites => selected (Oct. 2014) Hope & expectations Confirm POET findings (global strategy) Be more specific for multi-susceptible staphylococci IE Merge data with POET?

45 Conclusion (1): facts Infective endocarditis is a demanding disease with many therapeutic requirement Convincing data that: duration should be as stated in guidelines bactericidal regimens requested initially Data less robust Do we need to be i.v. & bactericidal throughout treatment? => A new concept for IE: induction / maintenance (onco)

46 Conclusion (2): prospects Clinical trials on oral switch POET could validate the strategy RODEO would be confirmatory, with enhanced power to conclude on multi-susceptible staphylococcal IE Other simplification trials? in 2015, need to be non-inferiority => n > 300 funding is an issue (limited interest for pharmaceutical companies)

47 Conclusion (3): prospects Meanwhile.. A growing number of patients are treated with oral switch Provided: early improvement with standard treatment (clinical, blood cultures, CRP) oral drugs available (PK/PD) adherence not an issue Observational studies on oral switch outcome warranted (series, analysis of failures)

48 Merci de votre attention!