Ba c te ra e mia o r se ve re se psis a s indic a tio n? BJ R - PowerPoint PPT Presentation

E MA me e ting Oc to b e r 2012 Ba c te ra e mia o r se ve re se psis a s indic a tio n? BJ R ijnde r s, MD, PhD Ye s we c a n (a nd sho uld)! De p. Inte r na l Me dic ine Se c tion of Inf Dis E r a smus MC R otte r dam, NL

Is it possible to include a sufficient amount of patients with clinically significant bacteremia in phase III studies? 200 YES 400 ? >500 ? >1000 ? Most recent EMA “approval” on IV antibiotic : Ceftaroline cSSSI (n=693): N=29 (4%) with bacteraemia Severe infections? 0.4% mortality (n=3, cancer, cardiac/ respiratory failure) CAP (n=580): N=23 (4%) with bacteremia Severe? PORT risk class III and IV Mortality 2.4% (n=15) 2

I nflue nc e o f e a rly T HE RAPY o n o utc o me ? Inappropriate Initial Antimicrobial Therapy and Its Effect on Survival in a Clinical Trial of Immunomodulating Therapy for Severe Sepsis N=904 microbiologically confirmed severe sepsis/septic shock 468 patients (52%) with documented BSI ! 28d mortality: 24% (168/ 693) when adequately treated versus 39% (82/211) with inappropriate initial AB therapy ( P< 0.001) => 38% relative or 15% absolute mortality reduction Am J Med. 2003;115:529 – 535 3

I nflue nc e o f e a rly T HE RAPY o n o utc o me ? Adequacy of Early Empiric Antibiotic Treatment and Survival in Severe Sepsis: Experience from the MONARCS Trial 24% relative 10% Absolute Mortality reduction ! 4 Ma c Arthur RD e t a l. Clin I nf Dis 2004

I nflue nc e o f e a rly T HE RAPY o n o utc o me ? Adequacy of Early Empiric Antibiotic Treatment and Survival in Severe Sepsis: Experience from the MONARCS Trial. = 1040 patients with BSI: 568 primary ! Ma c Arthur RD e t a l. Clin I nf Dis 2004 5

I nflue nc e o f e a rly T HE RAPY o n o utc o me ? Despite heterogeneity of the cause/source of the sepsis/bacteremia: Treatment effect of appropriate versus inappropriate therapy = clear 6

CRBSI CL ABSI IABD E ndoc ar ditis CAP UT I Bac te r e mia Oste omye litis SSSI Me ningitis 7

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Wha t’ s the pro b le m if ne w AB is use d fo r b a c te re mia / se psis o f unkno wn so urc e a s lo ng a s this a g e nt wa s we ll-studie d in this pa tie nt po pula tio n? => Clinic ia ns do this a ll the time a s 1/ 3th o r mo re o f c a se s o f se psis a t the E R a re initia lly o f unkno wn o rig in => Ofc o urse huma n PK a nd the b e st a va ila b le a nima l PK PD da ta a t le a st fo r the mo st fre q ue nt c a use s o f se psis a re a c o nditio sine q ua no n => Study pro to c o l c o uld ma nda te switc h to a ppro ve d drug whe n so urc e o f b a c te re mia b e c o me s c le a r during fo llo w-up 9

With re g a rd s to S. a ure us BSI : infe c tio n site re ma ins unkno wn in sub sta ntia l pro po rtio n o f pts, with prima ry b a c te ra e mia in up to t 33% o f c a se s whic h me a ns tha t a sig nific a nt pa rt o f the se se rio us infe c tio ns a re no t c o ve re d b y site -spe c ific indic a tio ns. Study o f line zo lid fo r CRBSI c a n b e se e n a s “a se psis/ b a c te re mia witho ut a kno wn so urc e study” a s o nly 23% o f the 735 inc lude d pts turne d o ut to ha ve CRBSI => Clin I nfe c t Dis. 2009 Ja n 15;48(2):203-12 10

23%

Study o f line zo lid fo r CRBSI c a n b e se e n a s “a se psis/ b a c te re mia witho ut a kno wn so urc e study” a s o nly 23% o f the 735 inc lude d pts turne d o ut to ha ve CRBSI => We le a rnt tha t line zo lid +- a zthre o na m/ a mika c in sho uld no t b e use d in this se tting 12 Clin I nfe c t Dis. 2009 Ja n 15;48(2):203-12

Study o f line zo lid fo r CRBSI c a n b e se e n a s “a se psis/ b a c te re mia witho ut a kno wn so urc e study” a s o nly 23% o f the 735 inc lude d pts turne d o ut to ha ve CRBSI => We le a rnt tha t line zo lid +- a zthre o na m/ a mika c in sho uld no t b e use d in this se tting => Po ssib ly o the r AB use d fo r e mpiric the ra py o f se psis a re infe rio r to o the rs. T ria ls tha t study the e ffic a c y o f a drug fo r se psis/ b a c te re mia witho ut a so urc e c o uld b e c o me “g a me c ha ng e rs” a nd impro ve c a re o f this life -thre a te ning c linic a l syndro me . 13 Clin I nfe c t Dis. 2009 Ja n 15;48(2):203-12

E .g . do c ume nta tio n o f e ffic a c y fo r se ve re se psis/ b a c te re mia o f c e fta ro line +- a ztre o na m/ a mino g lyc o side wo uld b e ve ry we llc o me . T he drug is a lre a dy a ppro ve d fo r CAP a nd c SSI : => Pts c o uld c o ntinue the drug a s dia g no sis o f c SSI o r CAP b e c o me s c le a r => Pts re spo nding to the ra py witho ut dia g no sis o f so urc e c o ntinue a s we ll => Pts with dia g no sis o f no n-a ppro ve d indic a tio n during the ra py c a n switc h to a ppro ve d R/ 14

…. …. ⇒ T he ma na g e me nt o f ne utro pe nic pa tie nts with fe ve r c a n b e a la b e le d indic a tio n ⇒ Why sho uld the tre a tme nt o f (se ve re ) se psis/ b a c te re mia o f unkno wn so urc e no t b e c o me a la b e le d indic a tio n a s we ll? 15

Not a good indication to study: Suspected CRBSI: As low as 10% are confirmed to have CRBSI at the end CRBSI in general: Coag neg staph = self-limiting if CVC is removed. Non-inferiority does not prove efficacy Good indication: CRBSI or CLABSI with S. aureus, but CVC removal should be obligatory Primary S. aureus BSI 16

Other possible future indications that should be strongly considered: • Severe sepsis of unknown origin or primary BSI in general T o sta rt o n the sa fe site : drug o f whic h e ffic a c y fo r so me o f the c a use s o f se psis a nd b a c te ra e mia is a lre a dy do c ume nte d (SSSI , UT I , CAP) I f la te r so urc e is ide ntifie d: a ppro pria te / spe c ific “fo r indic a tio n a ppro ve d” the ra py c a n b e g ive n (e .g . F Q fo r UT I ) • E mpir ic the r apy fo r se psis / bac te r ae mia in c hr o nic he mo dialysis patie nts + Mo rb idity mo rta lity is hig h a nd S. a ure us BSI fre q ue nt in the se pa tie nts + Study po pula tio n / c e nte rs a re we ll-de fine d Co ntro l: I V va nc o myc ine (o r c e fa zo le if MRSA<5%) +- a ztre o na m 17

F o r VRE / MRSA a nd po ssib le a lso g ra m-ne g a tive MO: Mo le c ula r te c hniq ue s will e na b le pro mpt inc lusio n up to 48hrs e a rlie r! 18

I ho pe I ha ve c o nvinc e d yo u tha t: 1. Suffic ie ntly la rg e studie s sho uld b e po ssib le 2. T he re is a urg e nt me dic a l ne e d fo r the se studie s a s the c urre nt ma na g e me nt o f the se pa tie nts is no t e vide nc e b a se d 3. A we ll tho ug ht-o ut de sig n c a n a vo id mo st o f the hurdle s. 19