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Jul 01, 2023 339 likes •669 views

Bezlotoxumab (Zinplava) as Adjunct Treatment for Clostridium difficile Janel Liane Cala, RPh Medical Center Hospital Objectives Review pathophysiology, risk factors, prevention, and treatment options of Clostridium difficile Infection (CDI)

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Bezlotoxumab (Zinplava) as Adjunct Treatment for Clostridium difficile

Janel Liane Cala, RPh Medical Center Hospital

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Objectives

  • Review pathophysiology, risk factors, prevention, and treatment
  • ptions 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)
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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 https://www.idsociety.org/uploadedFiles/IDSA/Guidelines-Patient_Care/PDF_Library/cdiff2010a.pdf

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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 https://www.idsociety.org/uploadedFiles/IDSA/Guidelines-Patient_Care/PDF_Library/cdiff2010a.pdf

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Poutanen et al. (2004). Clostridium dificile Associated Diarrhea in Adults. Canadian Medical Association Journal. Retrieved from http://www.cmaj.ca/content/171/1/51.full.pdf+html.

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CDI: Virulence Factors

Toxins A and B – 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

Poutanen et al. (2004). Clostridium dificile Associated Diarrhea in Adults. Canadian Medical Association Journal. Retrieved from http://www.cmaj.ca/content/171/1/51.full.pdf+html.

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

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CDI: Prevalence

  • Asymptomatic colonization

– 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 10 000 patient- days

Cohen, SH et al. (2010). Clinical Practice Guidelines for Clostridium dificile Infection in Adults. Infectious Disease Society of America. Retrieved from https://www.idsociety.org/uploadedFiles/IDSA/Guidelines-Patient_Care/PDF_Library/cdiff2010a.pdf

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  • 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

CDI: Diagnosis

Cohen, SH et al. (2010). Clinical Practice Guidelines for Clostridium dificile Infection in Adults. Infectious Disease Society of America. Retrieved from https://www.idsociety.org/uploadedFiles/IDSA/Guidelines-Patient_Care/PDF_Library/cdiff2010a.pdf

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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 24- 48 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 http://www.cmaj.ca/content/171/1/51.full.

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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 https://www.idsociety.org/uploadedFiles/IDSA/Guidelines-Patient_Care/PDF_Library/cdiff2010a.pdf

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CLINICAL DEFINITION SUPPORTIVE CLINICAL DATA RECOMMENDED TREATMENT ADVERSE EFFECTS INITIAL EPISODE (MILD TO MODERATE) WBC <15K SCr < 1.5 x premorbid level Metronidazole 500mg PO TID Neurotoxicity- seizures, neuropathy, encephalopathy Metallic Taste INITIAL EPISODE (SEVERE) WBC >15K SCr > 1.5 x premorbid level Vancomycin 125mg PO QID Nephrotoxicity Ototoxicity Infusion reaction (Redman Syndrome) INITIAL EPISODE (SEVERE, COMPLICATED) Hypotension, shock, ileus Vancomycin 500mg PO/NGT QID + Metronidazole 500mg IV TID Complete ileus: Vancomycin Retention Enema Vancomycin 500 mg / 100 ml NS Q6H 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 https://www.idsociety.org/uploadedFiles/IDSA/Guidelines-Patient_Care/PDF_Library/cdiff2010a.pdf

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ANTIBIOTIC COST PER DOSE REGIMEN COST PER 10 DAY REGIMEN Metronidazole 500 mg $ 0.73 500 mg TID $ 22 Vancomycin 125 mg pills $ 17 125 mg QID $ 680 Vancomycin 125 mg IV (compounded for oral) $ 2.50 - $10 125 mg QID $ 100 - $ 400 Fidaxomicin 200 mg $ 140 200 mg BID $ 2800

Surawicx, CM et al. (2013). Guidelines for Diagnosis, Treatment, and Prevention of Clostridium dificile Infections. American College of Gastroenterology. Retrieved from https://gi.org/guideline/diagnosis-and-management-of-c-difficile-associated-diarrhea-and-colitis/

Fidaxomycin - binds to and prevents movement of the "switch regions" of bacterial RNA polymerase

  • recurrent CDAD; failure from Metronidazole/ Vancomycin
  • 200 mg PO BID x 10 days
  • no renal adjustment needed
  • high cost
  • minimal systemic absorption; narrow spectrum of activity
  • ADV: N/V/ abdominal pain
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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 ~50 000

  • 1st 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 https://www.idsociety.org/uploadedFiles/IDSA/Guidelines-Patient_Care/PDF_Library/cdiff2010a.pdf

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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 http://www.cmaj.ca/content/171/1/51.full.pdf+html.

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CDI: Adjunct Treatment

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  • 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 0.2- 5 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

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  • Cl = 0.317 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

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Bezlotoxumab for Prevention of Recurrent Clostridium dificile infection (MODIFY I and II)

Wilcox, MH et al. NEJM 2017; 376:305-317

MODIFY: MONOCLONAL ANTIBODIES FOR C. DIFICILE THERAPY

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– Randomized, double-blind, placebo controlled trials – 322 sites, 30 countries from November 2011 - May 2015 – Protocols and amendments were approved by the IRB or independent ethics committee at each study site

Study Design

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

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Methods

PARTICIPANTS (2655)

BEZLOTOXUMAB

ACTOXUMAB + BEZLOTOXUMAB

ACTOXUMAB

10 MG/KG SINGLE DOSE 10 MG/KG SINGLE DOSE OF EACH

  • 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

  • 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

10 MG/KG SINGLE DOSE

BEZLOTOXUMAB

PLACEBO 0.9% SALINE

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Methods

PARTICIPANTS (N = 2559)

BEZLOTOXUMAB

ACTOXUMAB + BEZLOTOXUMAB

(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

(N = 781)

BEZLOTOXUMAB

PLACEBO (N = 773)

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  • 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.

  • 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

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  • 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

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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.

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Strengths

  • 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

Weakness

  • 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

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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

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QUESTIONS