Fidaxomicin Vs Vancomycin For Clostridium Difficile .

FidaxomicinFidi i vs VVancomycini fforClostridium difficile InfectionGERIATRIC GRAND ROUNDSJOURNAL CLUB9/21/12CARLY LAM M.D.PGY IVN ENGL J MEDVOLUME 364(5):422-431FEBRUARY 3, 2011LOUIE ET. AL

Overview Since 1990s 2x incidenceCdiff infection 3million cases/yr in US most common bacterialcause off didiarrheah iin US incidence, severity,mortality and infection inprior low risk population(young, healthy, communitydwelling, peripartum) clinical response tovancomycin/flagyl with p ratesrelapse

Overview new hypervirulent strain NAP1/BI/027 Emergence strongly correlates with fluoroquinolonesProduces more exotoxin A/B and additional binary toxin moreserious,, refractoryy infection with rates toxic megacolongrequiringqgcolectomy But not all treatment failure and relapse due to BI-strainBI strain

BI/NAP1 Strain C.diff

Clostridium difficile Increasingg nosocomial incidence severityy especiallypyif 65 y/o 20-50% adult carriers in hospitals and long term care facilities20%% patientsiwithi h stooll culturelnegativei on admissiond i i bbecomeinfected during hospitalization Especially severe infxn if Comorbidities eg. Advanced age Disturbed gut normal flora (eg. Antibiotics, antitumor meds)

Clostridium difficile 4 clinical forms Short-term colonization-usually develop in health care facility Acute diarrheadi hmild-severeild Fulminant diarrhea /- pseudomembranous colitis Toxic megacolon

Treatment Guidelines Infectious Disease Societyy of America ((IDSA)) Mild-mod:Severe:Metronidazole IV/POVancomycin POAGENTDOSAGEREGIMENCOST PERDOSECOST PER TXCOURSEMetronidazole500mg po TID x10-14d 0 73 0.73 21.90 2190 (10d),(10d) 30.66 (14d)Vancomycin125mg po QID x10-14d0 4d 31.83 1273 (10d), 1782(14d) 78 ( 4d)

TreatmentMetronidazoleVancomycin biliary excreted fecal Poor GIT absorption maxconcentrationt ti bbutt llargeamount absorbed by gut low drug levels atmucosal/intraluminall/i t l i l llevell Thus, high failure rate Complications-dose-depperipheral neuropathy,nausea, metallic taste NOT FDA-approvedppfortreatment C.diff infectionsconcentrationt ti iintracolonicallytl i ll Complications- systemicabsorption Renal tox

Treatment failure After successful initial treatment with flagylgy orvancomycin 20-30% recurrent Cdiff w/in 60days(usually 1st 2 weeks) Retreatment with either med resolves infection inmost patients but 1/3 have / 1 more recurrence,increases morbidity/mortality Risk factors for recurrence 65 y/oy/o, severe underlyingcomorbidities(immunosuppression, increase risk of requiringantibiotics/hospitalization), gastric acid suppression, need forongoing antibiotics during treatment for cdiff

Treatment Failure/Recurrence Increased frequencyqy of recurrent disease inhospitalized and outpatients creates pathogenreservoir leading to secondary infxn in other exposedpatientsti t

Fidaxomicin Macroclide, hydrolyzed to active metabolite Bactericidal; inhibits RNA polymerase Narrow spectrum-GP esp Cdiff, most staph, enterococci;no GN/fungi No cross-resistance with other antibx 8x more active in vitro than vancomycinyagainstgCdiffincluding NAP1/BI/027 strain Minimal systemic absorption High fecal concentrationless disruption of gut normal floraThus, highly active and more selective therapy against CdiffAnd possibly less systemic side effects

Study Design Prospective,p, multicenter,, double-blind,, randomized,,parallel group trial May 6, 2006- August 21, 2008 Phase 3 noninferiority study comparing efficacy andsafety of fidaxomicin with vancomyin in treatment ofCdiff infection

Study Population 552 US sites,, 155 Canadian sites Eligibility criteria: / / 16 y/oy/ Diagnosed with CdiffDiarrhea change in bowel habits 3 unformed BM /24h periodbefore randomizationrandomization, AND Cdiff toxin A/B/both in stool within 48h before randomization Could have received MAX 4 doses flagyl or vancomycin in24h period before randomization NOT on potentially effective concurrent treatment forCdiff (eg.(eg Bacitracin POPO, fusidic acidacid, rifaximin)

Exclusion Criteria life threatening or fulminant Cdiff infxn Wbc 30k, T 104F, sbp 90, septic shock, peritoneal signs, significantdehydrationToxic megacolong Past exposure to fidaxomicin Pregnancy or breastfeeding Ulcerative colitis/crohn’s 1 occurrence Cdiff w/in 3mths before start of study LikelihoodLik lih d off deathd h w/in/i 72hh fromfany cause

Randomization and Treatment Stratified based on whether current Cdiff FIRST EPISODE ((primaryioccurrence)) vs. SECOND EPISODE (fi(first recurrence))w/in 3mths before start of studyComputer generated randomization # and medication kit #assigned to each patientAssessed qd for clinical cure vs. failure x 10d therapyPatients given study medication daily PO q6h x 10 d Fidaxomicin 200mg PO q12h with intervening placebo, OR Vancomycin 125mg PO q6hIff met criteria clinicalll cure assessedd ffor recurrence q wkk x 28ddafter last dose study med if ( ) diarrhea, to notify study team reassess immediately

Definitions Clinical cure ResolutionRl i diarrheadi h (( / /3 unformed stools /2consecutive days)Maintain resolution w/oneed restart Cdiff therapybyy 2nd dayy after completepcourse therapy(investigator’s opinion)Marked #unformed stool atend therapy but residual mildab discomfort w/o need moreCdiff therapy (investigator(investigator’ssopinion) Clinical failure PersistentPidiarrheadi hNeed for more CdifftherapyInvestigator’s opinion

Definitions Global cure ResolutionRl i diarrheadi h w/o/recurrence Patients who stayed instudy, had follow upstudyassessment D36-D40after randomization wereassessed for recurrence Clinical recurrence 3 diarrhealdi h l stools/24hl / hwithin 4 weeks aftercompleting therapy( ) stool Cdiff toxinA/B/bothNeeded retreatment Cdiff

Outcomes Primaryy efficacyy end ppoint Rate clinical cure in Modified-intention-to-treat (mITT) Perprotocol (PP) population at end therapy or at time earlywithdrawal from study With documented adherence to protocol and had end-oftherapy evaluation Secondary efficacy end point Recurrence Cdiff w/in 4 weeks after end therapy Global cure in mITT PP

Safety Assessed from day informed consent – last dose studydrug given or last study visit (whichever came later) Physical exam, EKG, CBC, BMP, UA Adversedevents reported,d iff once per patient counteddonly as single incidence for particular adverse event Common adverse events: nausea,nausea vomitingvomiting, ab painpain,anemia, neutropenia. But no subject withdrew due tointolerance or allergy to study medication

Results Noninferiority study used one-sided lower 97.5% CI toanalyze primary end point , with noninferiority margin of-10%points Primary end point of clinical cure in both mITT PPmet noninferiority criterion. In mITT: 88.2% fidaxomicingroup, 85% vancomycin group (lower boundary 97.5% CIfor difference cure rates -3.1% points), PP: 92.1%fidfidaxomicini i group, 889.8%8% vancomycini group (l(lowerboundary of 97.5%CI of -2.6% points)

Clinical OutcomeRates of Primary and Secondary Endpoints

Results Secondary end point analysis -Fidaxomicin associatedwith significantly lower rate of recurrence thanvancomycin in both mITT (15.4% vs. 25.3%; a reductionwith fidaxomicin of 9.9%9 9% points; 95%CI95%CI, -16.6-16 6 to -2.9,-2 9 p 0.005) and PP (13.3% vs. 24.0%; a reduction withfidaxomicin of 10.7% points; 95%CI, -17 to -3.3;p 0.004)

Clinical Outcome

Results In PP ppopulationpBI-strain: similar rates recurrencein fidaxomicin 24.4%, vancomycin 23.6%(p 0.93) In PP population Non-BI strains: lower raterecurrence fidaxomicin 7.8% vs. vancomycin 25.5%( d ti with(reductionith fidfidaxomicini i off 17.7%% points;i t 95%CI,%CI-27.5 to -7.9; p 0.001)

Safety No significantgdifference rate adverse events orserious adverse events between fidaxomicin andvancomycin groups Occurrence any adverse event 62.3% fidaxomicin,60.4% vancomycin; serious adverse event 25.0%

Conclusion This phase 3 randomized clinical trial found the rate ofclinical cure of Cdiff infections with fidaxomicin wasnoninferior to vancomycin Fidaxomicin was associated with significantly lower rateof recurrence of Cdiff infection with nonnon-NAP1/BI/027NAP1/BI/027strain within 4 weeks after conclusion of treatment

Discussion Pros Fidaxomicinidi i BID PO vs. QID vancomyciniBacteriocidal vs. bacteriostatic Prolong postantibx effect may prevent relapse over longer periodNo plasma accumulationDoes not kill gut NF maintaining “colonization resistance” Prevents intro or persistence of pathogens and may inhibit reemergenceCdiff Theoretically decreases selection for overgrowth of vanc-resistantenterococciVancomycin sparing effecteffect decr rate of VREOverall similar effectiveness wrt clinical resolution acute diarrhea 2/2 Cdiffbut more sustained/durable resolution dz (improved global cure) withfidaxomicin

Discussion Cons Funded by Optimer Pharmaceuticals who manufactures drug 1st version of paper written by part-time employee of OptimerPharmaceuticals Excluded severely ill-toxic megacolon Data presentation and writing style highly biased Relative Risk reduction calculated rather than AttributableRelative Risk?ability to involve sicker patients in next study as not shown togdifference in clinical cure ratehave statisticallyy significantcompared to vancomycin in either modified intention-to-treat orper-protocol populations

Discussion Concern for oral flagyl or vancomycin inducedvancomycin-resistant enterococci Problematic issue with Cdiff infection is rate ofrecurrence andd itits associatedi t d morbidity,bidit mortality.t litFidaxomicin is noninferior to vancomycin in rate ofclinical cure,, has moderate absolute reduction ofrecurrence but it is drastically more expensive (1 tab 168, therapy course 3360) and no IDSA guidelines aswhen to implent Fidaxomicin.Fidaxomicin To consider use in individuals with severe or recurrentyallergygydisease with vancomycin

Bibiliography Louie et al., Fidaxomicin versus Vancomycin for Clostridium difficilediffiil Infection.f iNEJM 2011; 364 ((5):) 422-431Herbert L. Dupont, M.D., The Search for Effective Treatment ofClostridium difficile infection. NEJM 2011;364:473-475Pagano, M., Gauvreau, K., Principles of Biostatistics, 2nd edition2000University of Utah, Pharmacology department, FidaxomicinSears et al., Fidaxomicin Attains High Fecal Concentrations WithMinimal Plasma Concentrations Following Oral Administration inPatients With Clostridium difficile Infection; Clin Infect DisDis. 2012Aug 1;55

CARLY LAM M.D. PGY IV N ENGL J MED VOLUME 364(5):422-431 FEBRUARY FEBRUARY 3, 2011 LOUIE ET. AL. Overview . Pagano, M., Gauvreau