Bonnasot et al, have reviewed the risk of C difficile diarrhoea associated with specific antibiotics

The population studied: 92 patients aged >75y hospitalised for acute pneumonia, who subsequently developed C difficile diarrhoea (CDAD) in a French university hospital between 2007 and 2017.
Control population: 213 patients aged >75y admitted in the same hospital, with a diagnosis of acute pneumonia but did not develop CDAD, between November 1st 2012 and June 1st 2013.

The assessment was done on:
1. Which antibiotic had a lower incidence of CDAD
2. in hospital and one-year mortality.

Penicillin-beta-lactamase inhibitor  (OR = 0.43 (0.19-0.99); p = 0.05) was associated with a lower risk of CDAD than other antibiotic regimens.
After adjustment of the confounders, the CDAD was associated with a two-fold increase in hospital {OR (95%CI): 1.95 (1.06-3.58)} and one-year {OR (95% CI): 2.02 (1.43-7.31)} mortality .
Other observation –
Association of CDAD with
number of antibiotic drugs (OR = 1.90 (1.17-3.06); p = 0.009).
with antibiotic duration (per day, OR = 1.04 (0.96-1.11); p = 0.4).
hospitalization in the past 6 months (OR = 3.23 (1.43-7.31); p = 0.005),
hospitalization in the geriatrics department (OR = 3.33 (1.52-7.31); p = 0.003),
hospitalization length (per day, OR = 1.02 (1.01-1.04); p = 0.04), and
use of immunosuppressive drugs (OR = 2.91 (1.00-8.49); p = 0.05).

Ref: Bonnassot et al, Clostridioides difficile infection after pneumonia in older patients: Which antibiotic is at lower risk?, Journal of Hospital Infection, May 10, 2020 (article in press)

C difficile diarrhoea (CDAD)

– Caused by Clostridioides difficile (previously called Clostridium difficile).
– Anaerobic, spore-forming, gram-positive bacilli.
– C difficile (CD) can be present in healthy people without causing any symptoms (adults -3%, Children – 66%).
– It can also be found in soil, water and especially in the healthcare environment.
– Although the relationship between the antibiotic-associated pseudomembranous colitis and CD was discovered in the 1970s, it emerged as significant healthcare-associated infection due to the emergence of hypervirulent NAP1/BI/027 strain, (associated with high mortality) in 2000. [McDonald et al, NEJM, 2005]

Scanning electron microscopy picture of C difficile.
CDC/ Lois S. Wiggs –

C difficile diarrhoea and the concept of colonisation resistance.

Two essential factors are required for someone to acquire C difficile diarrhoea:
1. exposure to C difficile spore
2. disruption of the bowel microbiota

Exposure to the C difficile spore:

C difficile produces a spore which is capable of infecting people and can survive in the environment for a long time. The Spores can be present in large numbers in the environment surrounding a patient infected with C difficile. Unfortunately, the spores cannot be killed by alcohol hand sanitiser. To prevent these spore from reaching from the infected patient to a non-infected patient, it is essential to:

1. Anyone looking after the infected patient washes their hand with soap and water to remove the spores. Otherwise, they may carry the spore to others or infect themselves.

2. To keep the infected patient isolated in a room (prefer. negative pressure room) until the risk of spore dispersion decreases (until diarrhoea settle down).

It is important to remember the patient may still contain spores in their bowel after the symptoms have improved. However, it is easier to restrict the dispersion if there is no diarrhoea, and the patient can wash their hand after going to the toilet.

Disruption of the gut microbiota

Out gut contains 100 trillion micro-organisms (gut microbiota), mostly bacteria. Healthy gut microbiota helps us with glucose and energy metabolism, appetite regulation, bile acid metabolism etc. [Valdes, BMJ, 2018].

However, another primary function of these gut microbiota is providing “colonisation resistance“.

The population of the helpful bacteria of a healthy gut prevent harmful bacteria from getting a foothold. This is called colonisation resistance. So if this population is disrupted C difficile spore find it easier to settle down.

A standard method by which the disruption occurs is the use of antibiotic.

Although antibiotics are used to treat infection, often in a different area than gut, e.g. chest infection – antibiotics are non-selective. They not only kill the harmful bacteria in the site of disease but also kills the helpful bacteria in the gut. The paper by Bonnasot found that the risk increases with the number of antibiotics used.  



Which antibiotics have the highest risk?

Any antibiotic can disrupt the bowel microbiota and can predispose C difficile diarrhoea, in essence, any antibiotic can predispose C difficile diarrhoea. Reducing unnecessary antibiotic use is essential.

Fluoroquinolone (Ciprofloxacin, Levofloxacin, Moxifloxacin), 

3rd and 4th generation cephalosporins, 

clindamycin and 

carbapenems (e.g. meropenem)  –   are associated with the highest risk

[Hensgens et al, JAC, 2012][Pepin et al, CID, 2005][Johnson, NEJM, 1999][Thibault, ICHE, 1991][Loo, NEJM,2005] [Muto, ICHE, 2005][Clostridium difficile infection: How to deal with the problem]

It has been found that even a single dose of antibiotic can predispose to CDAD; however, a higher risk is associated with – multiple antibiotic and more prolonged duration [Pepin, CID, 2005]. The risk remains up to 3 months after the cessation of antibiotic. The risk is higher during the treatment and up to 1 month after cessation of antibiotic [Hensgens, 2012].

The O27 hypervirulent strains are associated with fluoroquinolone use [McDonald, NEJM, 2005]. This strain is typically associated with severe disease, poor outcome and hospitalisation. 

Some antibiotics are considered to have a lower risk:

penicillin, and anti-pseudomonal penicillins, with or without a beta-lactamase inhibitor, vancomycin.

[Ref: Clostridium difficile infection: How to deal with the problem]

Some charts showing the number of C difficile cases, mortality and case fatality rate

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