Bezlotoxumab (Zinplava) as Adjunct Treatment for Clostridium difficile. Janel Liane Cala, RPh Medical Center Hospital

Transcription

1 Bezlotoxumab (Zinplava) as Adjunct Treatment for Clostridium difficile Janel Liane Cala, RPh Medical Center Hospital

2 Objectives Review pathophysiology, risk factors, prevention, and treatment options of Clostridium difficile Infection (CDI) Introduce Bezlotoxumab (Zinplava) as adjunct treatment for CDI including its indication, dosage, adverse effects Evaluating literature regarding the use of Bezlotoxumab (Zinplava)

3 CLOSTRIDIUM DIFICILE INFECTION Clostridium difficile- gram (+) ; anaerobic; spore forming rod CDI = diarrhea + positive stool sample +/- pseudomembranous colitis* Onset: median of 2-3 days Hx of antimicrobial/antineoplastic tx within 8 wks in a majority of patients Transmission: oral-fecal route; fomites (commodes, rectal thermometer) Watery diarrhea, lower abdominal pain, systemic symptoms (fever, anorexia, nausea, malaise, leukocytosis, CRP, Alb, occult colonic bleeding) Severely ill patients may have little or no diarrhea due to toxic megacolon and paralytic ileus (loss of colonic muscular tone) Cohen, SH et al. (2010). Clinical Practice Guidelines for Clostridium dificile Infection in Adults. Infectious Disease Society of America. Retrieved from

4 CDI: Risk Factors Advanced Age (>/= 65 years) Exposure to antimicrobial agents Cancer chemotherapy Duration of hospitalization Degree of exposure to other patients with CDI Acid- suppressing medications: PPI s, H2RA s Cohen, SH et al. (2010). Clinical Practice Guidelines for Clostridium dificile Infection in Adults. Infectious Disease Society of America. Retrieved from

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6 Poutanen et al. (2004). Clostridium dificile Associated Diarrhea in Adults. Canadian Medical Association Journal. Retrieved from

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8 Toxins A and B CDI: Virulence Factors Trigger the attraction and adhesion of PMNs inflammation of the mucosal lining and cellular necrosis, as well as increased peristalsis and capillary permeability, leading to diarrhea and colitis Induce production of TNF-a and proinflammatory IL, contributing to the associated inflammatory response and pseudomembrane formation Toxin B produces more potent damage to colonic mucosa compared to toxin A NAP1/BI/027 Hypervirulent strain has been linked to several outbreaks of severe disease in North America and Europe 16 fold increase in toxin A production and 23 fold increase in toxin B production Poutanen et al. (2004). Clostridium dificile Associated Diarrhea in Adults. Canadian Medical Association Journal. Retrieved from

9 Asymptomatic colonization CDI: Prevalence 7% 26% (adult in acute care facilities) 5% - 7% (elderly in LTCF) Patients who were recently colonized with C. difficile and who have a high serum antibody response to C. difficile toxins were usually protected against diarrhea and remained asymptomatic carriers (Kyne et al, 2001) Clostridium difficile Associated Diarrhea (CDAD) - Accounts for 20% - 30% of antibiotic associated diarrhea - Most commonly recognized cause of infectious diarrhea in healthcare settings - Not a reportable condition- few surveillance data - Incidence rates range from 3.8 to 9.5 cases per patient- days Cohen, SH et al. (2010). Clinical Practice Guidelines for Clostridium dificile Infection in Adults. Infectious Disease Society of America. Retrieved from

10 CDI: Diagnosis Test Sample: diarrheal (unformed) stool, unless (+) ileus Asymptomatic patients- testing not recommended IDSA and SHEA proposed a two-step testing process for CDI: Initial Screen : GDH (Glutamate Dehydrogenase) test GDH - constitutive enzyme produced in large amounts by all strains of CDI Very sensitive, but not very specific for toxigenic C. dificile Detects if C. dificile is present but not if bacteria is producing toxins Confirmatory tests: Cell cytotoxicity test Toxigenic stool culture PCR assays Cohen, SH et al. (2010). Clinical Practice Guidelines for Clostridium dificile Infection in Adults. Infectious Disease Society of America. Retrieved from

11 CDI: Diagnosis CONFIRMATORY TESTS: Cell Cytotoxicity test Tissue culture to detect C. difficile toxin Looks for effects of cytotoxin in human cells time consuming- takes hrs for results excellent specificity; decreased sensitivity Toxigenic Stool Culture Growing C. difficile in culture Excellent specificity & sensitivity; GOLD STANDARD Takes 2-3 days for results Polymerase Chain Reaction (PCR) Rapid, sensitive, expensive Poutanen et al. (2004). Clostridium dificile Associated Diarrhea in Adults. Canadian Medical Association Journal. Retrieved from

12 CDI: Prevention Contact precautions, gloves and gowns Hand washing- antimicrobial soap + water Environmental disinfection- chlorine-containing agents; sporicidal agents Antimicrobial Use: choice, duration, switching IV to PO Decrease (11.5 cases/mo to 3.33 cases/mo) of CDI incidence after decreasing use of Clindamycin (Climo et al) Restrict use of clindamycin and cephalosporins (except for surgical ppx) Probiotics- limited data Cohen, SH et al. (2010). Clinical Practice Guidelines for Clostridium dificile Infection in Adults. Infectious Disease Society of America. Retrieved from

13 CLINICAL DEFINITION SUPPORTIVE CLINICAL DATA RECOMMENDED TREATMENT ADVERSE EFFECTS INITIAL EPISODE (MILD TO MODERATE) INITIAL EPISODE (SEVERE) INITIAL EPISODE (SEVERE, COMPLICATED) WBC <15K SCr < 1.5 x premorbid level WBC >15K SCr > 1.5 x premorbid level Metronidazole 500mg PO TID Vancomycin 125mg PO QID Hypotension, shock, ileus Vancomycin 500mg PO/NGT QID + Metronidazole 500mg IV TID Complete ileus: Vancomycin Retention Enema Vancomycin 500 mg / 100 ml NS Q6H Neurotoxicity- seizures, neuropathy, encephalopathy Metallic Taste Nephrotoxicity Ototoxicity Infusion reaction (Redman Syndrome) Same as initial episode SECOND RECURRENCE Vancomycin tapered/pulsed regimen Cohen, SH et al. (2010). Clinical Practice Guidelines for Clostridium dificile Infection in Adults. Infectious Disease Society of America. Retrieved from

14 ANTIBIOTIC COST PER DOSE REGIMEN COST PER 10 DAY REGIMEN Metronidazole 500 mg $ mg TID $ 22 Vancomycin 125 mg pills $ mg QID $ 680 Vancomycin 125 mg IV (compounded for oral) $ $ mg QID $ $ 400 Fidaxomicin 200 mg $ mg BID $ 2800 Fidaxomycin - binds to and prevents movement of the "switch regions" of bacterial RNA polymerase - recurrent CDAD; failure from Metronidazole/ Vancomycin mg PO BID x 10 days - no renal adjustment needed - high cost - minimal systemic absorption; narrow spectrum of activity - ADV: N/V/ abdominal pain Surawicx, CM et al. (2013). Guidelines for Diagnosis, Treatment, and Prevention of Clostridium dificile Infections. American College of Gastroenterology. Retrieved from

15 CDI: Treatment DC causative antimicrobial ASAP Supportive tx : hydration, correction of electrolyte imbalance Antiperistaltic agents: not recommended; precipitate toxic megacolon Colectomy: for severely ill patients (toxic megacolon) perioperative mortality: Serum lactate >5 mmol/l; WBC ~ st Recurrence: same as initial episode 2nd recurrence: Vanc pulse dosing; avoid metronidazole (cumulative neurotoxicity) Fecal transplant: NGT/ enema; consider after 3 recurrences IVIG: used with success in a small number of patients with fulminant disease Cohen, SH et al. (2010). Clinical Practice Guidelines for Clostridium dificile Infection in Adults. Infectious Disease Society of America. Retrieved from

16 CDI: Recurrence Risk Factors: Age > 65 Increased severity of underlying disease Exposure to additional antibiotics after treatment Compromised immunity; Low serum antibody response to C. dificile toxin Multiple relapses: Rifaximin; Rifampin + Vanc; Rifampin + Colestipol/ Cholestyramine Circulating antitoxin antibodies are protective against primary and recurrent CDI (Leav et al, 2010) Poutanen et al. (2004). Clostridium dificile Associated Diarrhea in Adults. Canadian Medical Association Journal. Retrieved from

17 CDI: Adjunct Treatment

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19 Fully human IgG that binds to C difficile toxin B Indication: Patients >/= 18 yo receiveing CDI antibacterial therapy Product description: sterile, aqueaous, preservative-free solution Conc: 1000 mg /40 ml Compatible with: NS or D5W (maximum conc of 1 10 mg/ml) Dose: 10 mg/kg IV infusion over 60 minutes (single dose) Use a sterile, nonpyrogenic, low-protein binding micron filter upon administration Storage of diluted solution: Room temp for up to 16 hours (protected from light) Refrigerated (2C to 8C) for up to 24 hours Source: Bezlotoxumab (Zinplava) Prescribing Information- Merck Laboratories

20 Cl = L/day ; Vd = 7.33 L; t1/2 = 19 days Immunogenicity (Healthy subjects and CDI patents) no anti-drug antibody against Zinplava was observed following a single 10mg/kg administration Metabolism: Not metabolized by liver or excreted by kidneys Pharmacokinetics no clinically relevant effects of renal and/or hepatic impairment No dose adjustments are required beyond the weight-based dose Source: Bezlotoxumab (Zinplava) Prescribing Information- Merck Laboratories

21 Bezlotoxumab for Prevention of Recurrent Clostridium dificile infection (MODIFY I and II) Wilcox, MH et al. NEJM 2017; 376: MODIFY: MONOCLONAL ANTIBODIES FOR C. DIFICILE THERAPY

22 Study Design Randomized, double-blind, placebo controlled trials 322 sites, 30 countries from November May 2015 Protocols and amendments were approved by the IRB or independent ethics committee at each study site Inclusion criteria Adults (Age >/= 18) with primary or recurrent CDI Patients receiving SoC antibiotics (10-14 days) Presence of diarrhea + stool test positive for toxigenic C. difficile Patients who have one or more risk factors for recurrent CDI Exclusion Criteria Chronic diarrheal illness, e.g. Ulcerative colitis, Crohns diseas Planned surgery for CDI within 24 hours Positive pregnancy test, Breast-feeding women Patients who received IVIG within 6 months prior to infusion of study drug Patients not expected to survive within 72 hours

23 Methods PARTICIPANTS (2655) Participants recorded unformed BM daily until Day 90 post infusion Safety assessments: Pre & post infusion EKG Monitoring reactions 24hrs after infusion Recording all adverse events through week 12 BEZLOTOXUMAB 10 MG/KG SINGLE DOSE ACTOXUMAB + BEZLOTOXUMAB 10 MG/KG SINGLE DOSE OF EACH PLACEBO 0.9% SALINE ACTOXUMAB 10 MG/KG SINGLE DOSE Actoxumab group was discontinued after MODIFY I: Rate of recurrence was significantly higher in Actoxumab VS Actoxumab + Bezlotoxumab group More deaths and adverse effects (25% sepsis) in Actoxumab VS Placebo

24 Methods BEZLOTOXUMAB (N = 781) PARTICIPANTS (N = 2559) ACTOXUMAB + BEZLOTOXUMAB (N = 773) PLACEBO (N = 773) 2655 participants 2559 were included in the modified intention-to-treat population Most common reasons for discontinuation Death (7%), Withdrawal of consent (4%), Loss to follow up (3%) In 94% of the patients, the study agent was infused within 6 days of initiation of SoC antibiotics Primary Endpoint: proportion of participants with recurrent CDI during 12 weeks of follow up

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26 The comparison of participants according to hospitalization status, SoC antibiotic therapy, and geographic region, the differences in rates of recurrent infection were consistent with those seen overall. Therefore, choice of SoC antibiotic has no discernible effect on Bezlotoxumab Rate of participants who had recurrent infection was significantly lower in the Bezlotoxumab (17%) and Actoxumab + Bezlotoxumab (15%) VS Placebo (27%) group. Effect of Bezlotoxumab and Actoxumab + Bezlotoxumab on rate of CDI recurrence has no significant difference.

27 Infusion- specific reactions (9%) Nausea (2%), Headache (2%), Dizziness (1%), Fatigue (1%), Pyrexia (1%) 4 weeks post infusion, overall rates of adverse events were similar: Bezlotoxumab (62%), Placebo (61%) Actoxumab- Bezlotoxumab (59%) *** Higher with Actoxumab (67%) CHF exacerbation was reported in CHF patients: Actoxumab- Bezlotoxumab (1%) Bezlotoxumab (2%) Actoxumab (1%), Placebo (2%) No binding or neutralizing antidrug Antibodies to bezlotoxumab were detected

28 Take Home Points Bezlotoxumab is not an antibacterial medication for the treatment of CDI. Bezlotoxumab is a monoclonal antibody indicated for patients >/= 18 yo who are receiving standard of care antibiotic treatment of CDI who are at high risk of recurrence Bezlotoxumab is a single dose, 60- minute infusion that needs to be administered with a micron filter. Bezlotoxumab has the safety profile similar to placebo and does not cause immunogenicity Actoxumab is not efficacious in decreasing rate of CDI recurrence and has no additional benefit when given in combination with Bezlotoxumab. Bezlotoxumab should be used with caution in patients with CHF or other cardiac conditions.

29 Weakness Cost effectiveness of Bezlotoxumab in comparison to other treatment of CDI recurrence (eg FMT, Fidaxomycin) Needs a larger and more diverse study population (in terms of race, pediatric age group, pregnancy, lactating women) Long term safety profile is yet unknown (teratogenicity, carcinogenicity) Efficacy of Bezlotoxumab in combination with treatments other than SoC Antibiotics (FMT) is not studied No further studies were done as to explain why there are higher rates of recurrence and adverse events in Actoxumab group Strengths MODIFY trials included a substantial percentage of participants (77%) who had one or more risk factor for recurrent CDI Although SoC antibiotics are not standardized, study groups were stratified according to SoC antibiotics to make it balanced

30 Conclusions Single IV dose of Bezlotoxumab given with SoC antibiotics provided protection against recurrent CDI for up to 12 weeks that was superior to that provided by SoC antibiotics alone It is proven in decreasing rate of CDI recurrence by 38% lower than that associated with SoC antibiotics alone Safety profile is similar to that of placebo Bezlotoxumab should not be expected to affect initial clinical cure. Efficacy of Bezlotoxumab in recurrent CDI is not affected by the choice of SoC antibiotics Effect on the rate of CDI recurrence were similar with Bezlotoxumab VS Actoxumab + Bezlotoxumab in all subgroups except those infected by strains 027, 078, or 244

31 QUESTIONS