Single or combinationBildbereich treatment of seriousBitte auf der S. Masterfolie aureus austauschen infections Siegbert Rieg Division of Infectious Diseases, Department of Medicine II & Center of Chronic Immunodeficiency (CCI) ESCMIDUniversity Medical eLibrary Center Freiburg, Germany © by author S. aureus – spectrum of serious infections osteoarticular infections & PJI complicated SSTI endocarditis deep-seated manifestations ESCMID eLibrary © by author (n=1493) community-acquired SAB healthcare-associated SAB 150 nosocomial SAB 100 50 SAB cases per year cases SAB 0 ESCMID2006 2007 2008eLibrary2009 2010 2011 2013 2014 2015 University Medical Center Freiburg Ingram,© Clinby Microbiol Infectauthor 2014 rationale for co-therapy in general synergistic effects (at least in vitro) bactericidal activity diminish potential resistance development S. aureus – specific reasons targeting intracellular reservoir effects on biofilm / devices decrease toxin production treatment of small colony variants preventESCMIDdissemination eLibrary © by author case #1 – 19yo male with bicuspid aortic valve History healthy student, 4 days prior to admission fever and chills no IVDA, no travel abroad, no other specific risk factors Clinical findings emergency department petechial lesions on palmes and soles, slight neck stiffness mental status changes Lab WBC 5000/µl, CRP 340 mg/L (<5mg/L), procalcitonin 52 ng/mL (<0.5 ng/mL), creatinin 2.1 mg/dL Cerebral CT scan on admission Subacute cerebellar ischemic lesion Blood cultures on admission S. aureus Oxa S Admission to neurology Lumbar puncture WBC 350/µl (95% PMNs), protein 0.64 g/L, S. aureus Oxa S TEE bicuspic aortic valve, 16 mm vegetation and grade III regurgitation ESCMID eLibrary © by author case #1 – 19yo male with bicuspid aortic valve Patient was initially treated with ceftriaxon, ampicillin and aciclovir What treatment would you recommend now? 1. Continue ceftriaxon and ampicillin 2. Switch to flucloxacillin adjusted to renal function 6g/d 3. Switch to flucloxacillin 8-12g/d 4. Switch to flucloxacillin 8-12g/d plus gentamicin 3 x 60 mg/d 5. Switch to flucloxacillin 8-12g/d plus rifampicin 2 x 450 mg/d ESCMID eLibrary © by author ESC and AHA endocarditis guidelines Staphylococcal native valve endocarditis ESCMID eLibrary Habib, Eur Heart© Journal by 2015 | Baddourauthor, Circulation 2015 co-therapy – in vitro evidence or ‚choosing the right model‘… susceptibility testing checkerboard test, time-kill studies, disc diffusion, E-test synergistic vs. additive effect vs. indifference vs. anatgonism rifampicin plus antistaph penicillins, cephalosporins synergy at subinhibitory rifa concentrations vs. indifference or anatagonism at higher concentrations vancomycin - antagonisitic or indifferent fluoroquinolones - synergy only at subinhibitory rifa concentrations linezolid - mostly additive effects noted animal models ESCMIDmouse vs. rat vs. rabbit endocarditis eLibrarymodel animal survival, sterilisation of vegetations vs. secondary foci Forrest , J Clin Microbiol 2010© | Nguyen by, JAC 2010 author | Perlroth, Arch Intern Med 2008 co-therapy in native valve endocarditis retrospect cohort analysis, 84 cases of native valve endocarditis standard vs. standard & rifampin co-therapy associated with longer bacteremia duration higher mortality and relapse drug interactions RCT of 42 patients MRSA endocarditis vanco mono vs. vanco & rifampin median duration bacteremia 9 vs. 7 days no significant difference in mortality native valve endocarditis – high inoculum infection, with biofilm formation ESCMIDand reduced susceptibility eLibrarywithin vegetation Riedel, ©AAC 2008 by | Levine, Annauthor Intern Med 1991 Survey on endocarditis treatment practices in large referral centers ESCMID eLibrary Tissot -Dupont,© ClinbyMicrobiol authorInfect 2017 (in press) case #1 – 19yo male with bicuspid aortic valve …complicated and fatal courseCT 18.12. MR 21.12. MR scan . embolisation with stroke & secondary hemorrhage . prolonged positive blood cultures (until day 9) . perivalvular abscess with perforation . progressive heart failure . patient died 12 days after presentation TEE 29.12. CT scan ESCMID eLibrary © by author case #2 – 79yo male with community-acquired SAB History metabolic syndrom with coronary artery disese, pain inguinal region/lower abdomen for 7 days, general malaise, episode of chills 5 days ago clinical findings emergency department slight pain on palpation symphysis pubis region, no other pertinent findings Lab WBC 13.000/µl, CRP 170 mg/L (<5mg/L), procalcitonin 0.9 ng/mL (<0.5 ng/mL) Pelvic CT scan slight edema in symphysis region Blood cultures on admission S. aureus Oxa S TTE & TEE no vegetations or other signs of endocarditis ESCMID eLibrary © by author case #2 – 79yo male with community-acquired SAB After having received blood culture results (MSSA), which treatment would you initiate? 1. Flucloxacillin 8g/d 2. Cefazolin 6g/d 3. Flucloxacillin 8g/24h plus rifampicin 900mg/d 4. Flucloxacillin 8g/24h plus fosfomycin 12g/d 5. Flucloxacillin 8g/24h plus levofloxacin 750mg/d ESCMID eLibrary © by author case #2 – 79yo male with community-acquired SAB History metabolic syndrom with coronary artery disese pain inguinal region/lower abdomen for 7 days, general malaise, episode of chills 5 days ago clinical findings emergency department slight pain on palpation symphysis pubis region, no other pertinent findings Lab WBC 13.000/µl, CRP 170 mg/L (<5mg/L), procalcitonin 0.9 ng/mL (<0.5 ng/mL) Pelvic CT scan slight edema in symphysis region Blood cultures on admission S. aureus Oxa S TTE & TEE no vegetations or other signs of endocarditis Bone scan and MRI symphysitis pubis …and we notice a pacemaker is in situ ESCMID eLibrary © by author case #2 – 79yo male with community-acquired SAB Knowing about the implanted foreign body/device, would you change the antibiotic regimen? 1. No, continue Flucloxacillin 8g/d 2. No, continue Cefazolin 6g/d 3. Add rifampicin 900mg/d 4. Add fosfomycin 12g/d 5. Add levofloxacin 750mg/d ESCMID eLibrary © by author co-therapy in S. aureus bacteremia comparative studies until 2011 ESCMID eLibrary ©Thwaites by, Lancet Infect authorDis 2011 co-therapy in S. aureus bacteremia comparative studies until 2011 ESCMID eLibrary Ruotsalainen ©, J Intern Medby2006 | Thwaitesauthor, Trials 2012 co-therapy in S. aureus bacteremia newer studies 357 patients surviving for at least 3 days primary endpoint day 90-mortality ESCMID eLibrary ©Forsblom by, PLoS One author2014 co-therapy in S. aureus bacteremia newer studies INSTINCT-cohort, post hoc-analysis (n=964) Monotherapy Combination therapy (MoRx) (CoRx) Cell-wall active agent MoRx plus rifampicin, (β-lactam, fluoroquinolone, vancomycin, fosfomycin or daptomycin) gentamicin a djustmentESCMIDfor survivor eLibrarybias ©Rieg, ClinbyMicrobiol Infectauthor2016 All patients (n=964), endpoint day 90-mortality Combination therapy (ref: no) 0.661 0.510 0.856 0.0017 withoutESCMIDadjustment for survivor eLibrarybias! ©Rieg, ClinbyMicrobiol Infectauthor2016 co-therapy in S. aureus bacteremia newer studies Subgroup analysis – day 90-mortality unchanged in com-acqu. SAB, disseminated SAB, severe sepsis/shock implanted foreign bodies/devices (n=344) HR 0.61 [CI 0.40-0.92] [prosth. heart valve, PM/ICD, vascular grafts, orthoped. prosthesis in situ] only rifampicin co-therapy (n=266) HR 0.55 [CI 0.33-0.91] recurrence within 180 days (bacteremic & non-bacteremic) in this subgroup 15/142 patients (10.6%) mono-therapy vs. 9/202 (4.5%) co-therapy (p=0.03) all butESCMID one without overt device infectioneLibraryin initial SAB ©Rieg, ClinbyMicrobiol Infectauthor2016 RCT in UK Adjunctive rifampicin in SAB 758 patients with MSSA/MRSA bacteremia randomized to either rifampicin 14d (600-900mg) vs. placebo Inclusion criteria: active antibiotic therapy ≤96h Primary endpoint: bacteriologically confirmed failure or death or recurrence within 12 weeks Patients included: age 65, Charlson score 2, com.-acquisition 64%, MRSAB 7% . 60% of patients with non deep-seated focus (iv-cath, SSTI, respiratory/urinary tract, unknown focus) . 40% of patients with deep-seated focus . 23% deep tissue abscess . 8% native joint ESCMID. 4% native / 2% prosthetic eLibraryheart valve . 5% implanted vascular device ©Late breaker bySession #OS0250Gauthor RCT in UK: Adjunctive rifampicin to reduce early mortality from Staphylococcus aureus bacteraemia (ARREST) Treatment duration 29 days, 85% antistaph. penicillin SAE comparable, more drug interaction & antibiotic modifying AEs in rifampicin group Prim. endpoint: failure/death or recurrence within 12w 62 events in rifampcin vs. 71 in placebo group (difference -1,4% [95% CI -7,1%; +4.2%]) HR 0,96 [95% CI 0,68-1,34], p=0.8 No signs of heterogeneity within 18 subgroups (p>0.05) ESCMID(enough patients in subgroups eLibrary of interest included?) ©Late breaker bySession #OS0250Gauthor RCT in UK: Adjunctive rifampicin to reduce early mortality from Staphylococcus aureus bacteraemia (ARREST) Endpoint recurrence bact. confirmed n=3 rifampicin vs. n=16 placebo (p=0.01) clin. confirmed n=8 rifampicin vs. n=22 placebo (p=0.01) NNT to prevent one recurrence = 29 (clin. conf. 26) Interpretation (so far) ‘uncompl.’ S. aureus bacteremia: no need for co-therapy focus superficial (iv-cath, SSTI), respirator and urogenital tract deep-seated manifestations/abscesses no final decision yet in specific subgroups implanted foreign bodies/devices ESCMIDnative/prosthetic valve endocarditis eLibrary © by author Thank you for your attention! Bildbereich Bitte auf der Masterfolie austauschen Siegbert Rieg Division of Infectious Diseases, Department of Medicine II & Center of Chronic Immunodeficiency (CCI) ESCMIDUniversity Medical eLibrary Center Freiburg, Germany © by author.