Clostridium difficileBy Bana Hadid

Medical care is supposed to help you, right?

•Well guess what?•Sometimes medical care can be harmful!•About 30-50% of antibiotic prescriptions are unnecessary or incorrect

One healthcare associated illness (HAI)is caused by the germ Clostridium difficile

• Gram-positive, spore-forming anaerobe• Caused almost half a million infections in the United

States in 2011• And 29,000 died within 30 days of the initial diagnosis• Most likely to occur between 3 and 5 days after

exposure to spores• 85% of nosocomial CDI cases occur within 1 month of

discharge from hospital

People most at risk

•Older adults, who have to take antibiotics for a long time and also get medical care [in hospitals]

Antibiotics • Kill ALL of the bacteria in our bodies• Bad AND good ones

• Therefore, good germs that protect against infection are destroyed for several months.• During this time, patients can get sick from C. difficile

What does C. difficile do?

•Causes colitis: inflammation of the colon by releasing toxins A & B•Toxins A and B both damage colonic cells

•The bacteria’s spores are found in feces

Transmission?

•People become infected if they touch things that have been contaminated with feces and then touch their mouth or other mucous membranes• Transmitted mainly via hands of health care personnel who have touched a contaminated surface•Wipe down high-touch areas with bleach wipes (worked in MayoClinic)

•C. difficile can live on surfaces for a long time• The germ is still potent when you do come in contact with a patient/person

Symptoms

•Watery diarrhea•Fever•Loss of appetite•Nausea•Abdominal pain/tenderness

Treatment

•When possible, stop other antibiotics•You have to give IV fluids and balance the patient’s electrolytes•Primary infection is treated with•Metronidazole•Vancomycin•Fidaxomycin

Treatment cont.

•Unfortunately, this isn’t always 100% effective• Recently, hypervirulent strains developed that’re resistant to most antibiotics• Infection returns in about 20% of patients• In small number of pts, infection returns over and over again

Treatment cont.•Another suggested treatment is• Stool transplant from healthy person to colon of infected patient• Seems to be the most effective method for patients with repeated infections• Not widely available• Long term safety not been established•Microbes are much easier to manipulate than human cells• Transplanting a microbiome is way easier than transplanting a kidney.

Treatment cont.• It is important to prevent this disease• It not only affects so many people, but it also creates a huge financial burden•No vaccine is currently available against C. Diff

Different vaccines Being Researched

•Active vaccination•Passive vaccination•Monoclonal antibodies•Carbohydrate-based Clostridium difficile vaccines•Fusion protein containing the receptor binding domains of C. difficile toxin A and toxin B•Anti-toxin A and anti-toxin B Vaccines Phase I and II trials

Phase I—initial safety studies•Healthy adult (18–55 years) or elderly (≥65 years) volunteers•Seroconversion: the time period during which antibodies develop and become detectable in the blood.•100% of adults who received any dose of the vaccine• Seroconversion after 2 doses for toxin A

•100% of elderly who received the highest dose of the vaccine• Seroconversion after 2 doses for toxin A

Phase I—initial safety studies cont.

•Robust seroconversion for anti-toxin A and B•Seroconversion occurred quickest in the highest dose•No volunteer receiving placebo seroconverted.•Most adverse events were mild or moderate

Phase I—initial safety studies cont.

•Acceptable safety and tolerability compared to placebo•Antibody titers decreased by Day 236•The response occurred more rapidly in younger than older volunteers• Immunity declined more markedly in the elderly, as generally observed in vaccine responses.

Phase II—optimization of dosage and schedule

•Stage I = assess the safety and immunogenicity of four combinations administered in the same schedule•Stage II = assessed two further schedules using the combination selected in Stage I•There were no safety issues.

Phase II—optimization of dosage and schedule cont.

•The high dose + adjuvant combination given at 0–7–30 days elicited the best immune response•Selected for further clinical development of the candidate vaccine

• In all groups there were very few immediate AEs•Most adverse reactions were mild Grade 1

Where do we go from here?

•The vaccine is being developed to be given prior to hospitalization (e.g. for elective surgery)•More doses = better immune responses•However, in practice, vaccination compliance would be better with a shorter schedule

Where do we go from here? Cont.

•Vaccine efficacy is currently being assessed in an ongoing, multinational Phase 3 efficacy study•CDIFFENSE STUDY •Began recruitment in August 2013•Will last approximately 4.5 years • 15,000 adults aged 50+

•Evaluates the safety, immunogenicity and efficacy of a toxoid A and B vaccine for the prevention of primary symptomatic C. difficile infection (CDI)

References•http://www.sciencedirect.com.revproxy.brown.edu/science/article/pii/S0264410X1200103X•http://www.sciencedirect.com/science/article/pii/S0264410X1600339X•http://www.sciencedirect.com.revproxy.brown.edu/science/article/pii/S0264410X12005762•https://www-scopus-com.revproxy.brown.edu/record/display.uri?eid=2-s2.0-84860573425&origin=inward&txGid=0 •http://gerryporter.blogspot.com/2012/08/microbes-maketh-man.html

References•https://www-scopus-com.revproxy.brown.edu/record/display.uri?eid=2-s2.0-84875960833&origin=inward&txGid=0•http://www.cdc.gov/hai/organisms/cdiff/Cdiff-patient.html•http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev3.pdf•http://www.sanofipasteur.com/en/Documents/PDF/Cdiffense%20Trial%20Fact%20Sheet_EN_updated%20with%20map.pdf