Emmanuel Nwankwo and Andrew Ward ask whether empirical antibiotic therapy can still be relied upon.
Clostridium difficile infection (CDIF) has established itself as the major nosocomial antibiotic-associated diarrhoeal infections in our hospitals today. Antibiotic therapy may predispose patients to CDIF by altering the gut normal microbiome, enabling the causative bacteria to dislodge the normal flora and colonise the patient intestinal tract. The progression of CDIF can lead to pseudomembranous colitis, toxic megacolon and perforation of the colon.
There have been many interventions in UK hospitals to reduce the spread of CDIF. Some of these interventions have been successful, but many have had limited success and contributed to the outbreaks of infectious diarrhoea in hospitals.
The cost of clinical isolation, treatment and management of CDIF in NHS hospitals places a significant burden on hospital finances, with Public Health England (PHE) annual statistics showing that between April 2015 and end of March 2016, more than 14,100 cases of CDIF were reported across all NHS hospitals in England, with an estimate of over £4,000 per case in the UK, which could be higher in the current financial climate. The NHS in Scotland estimated that between October 2015 and October 2016 there were 1,150 cases of CDIF, at a cost of more than £8.6m.
The gradual emergence of antimicrobial resistance in the treatment of CDIF has become a concern. It is estimated that there are about 10% to 30% of reoccurrences of CDIF in treated patients, which could be due to either a relapse of the first infection or re-infection by a different C. difficile strain. However, there have been a few treatment suggestions in multiple reoccurrences, including the use of higher dose of oral vancomycin on its own or in combination with rifampicin, albeit with the risk of potential increase in vancomycin resistant Enterococci infections. Faecal microbiota transplant is considered when all treatment options fail. This is the prompt reinstitution of healthy donor stool with possible disease resolution in 92% of cases.
Susceptible or not
From a 2018 study, 160 clinical faecal specimens of known C. difficile-colonised patients with diarrhoea were cultured on Colorex C. difficile chromogenic agar (E&O Laboratories Limited, Scotland).
After identification, the C. difficile strains were tested against a variety of antibiotics, using antimicrobial minimum inhibitory concentration (MIC) gradient strips, following the methodology recommended by EUCAST.
Metronidazole, vancomycin, rifampicin and clindamycin were chosen because of the emergence of their reduced susceptibility. Teicoplanin, levofloxacin and clindamycin were included to check their susceptibility rate in the local area of the hospital. The inclusion of a new broad-spectrum fifth-generation cephalosporin, ceftobiprole was to determine if C. difficile isolates are sensitive to the antibiotic, and so the introduction of this antimicrobial agent in the local hospital of this study should not significantly increase the risk of CDIF for patients. Ceftobiprole also has lesser potential than other broad-spectrum cephalosporins in promoting C. difficile growth and toxin production, due to its excretion route through the kidneys.
There are currently no EUCAST interpretation guidelines for determining the susceptibility to teicoplanin, rifampicin, ceftobiprole, levofloxacin, clindamycin and linezolid; however, information from similar research was used to determine the susceptibility rate of C. difficile.
Results
The prevalence of C. difficile resistance to the two first-line antimicrobial agents for treatment was found to be 22% for metronidazole, 16.6% for vancomycin and 8.3% for a combination of both. Low MICs were observed in linezolid (98%), teicoplanin (96.6%), rifampicin (89%) and clindamycin (53.8%) with observation of levofloxacin resistant rate of 63.4%. Ceftobiprole was shown to have a good activity against C. difficile with 79.3% MIC of ≤4 mg/L.
The average age of patients from the 160 faecal specimens used was 76 years, with 67.5% from female and 32.5% from male patients, with 54% recorded as being hospital in-patients and 46% community-acquired CDIF. However, we could not determine whether the number of in-patients was actually hospital acquired or community acquired, as this is a retrospective study.
This study included a new broad-spectrum fifth-generation cephalosporin, ceftobiprole, with the aim of showing that C. difficile isolates are sensitive to the antibiotic and so the introduction of this agent in the hospital of study should not significantly increase the risk of CDIF for in-patients.
However, that should not be the case, as not all antibiotics within a given class should be considered a risk factor to CDIF, as there are differences in pharmacokinetics and excretion routes with cephalosporins – as in the case of ceftobiprole, which is excreted via the kidney. Studies carried out by Ednie et al (2007), showed that ceftobiprole exhibits a good activity against C. difficile isolates, with MIC of 2-4 mg/L. Nerandzic et al, 2011, suggest through their study that ceftobiprole may have low tendency to promote CDIF due to its greater activity against C. difficile. Similar results were seen in a recent study, with 79.3% of ceftobiprole MIC of 2-4 mg/L and 20% MIC of >4 mg/L. Regardless of ceftobiprole’s good activity against the C. difficile strains obtained from this study and other studies, although a number of hindrances may play a role, which includes administration by IV infusion, the two-hour infusion time and cost.
The results of the author’s study may necessitate a review of empirical treatment of C. difficile.
There is also an apparent need to set up a periodic antimicrobial surveillance plan for CDIF, which will be helpful for optimising antimicrobial stewardship programmes in hospitals, especially in the treatment of CDIF and in particular with instances of increasing local treatment failures.
Emmanuel Nwankwo is a Specialist Biomedical Scientist
Andrew Peter Ward is a Senior Biomedical Scientist, both from the Microbiology Department at University Hospital of North Tees and Hartlepool NHS Foundation Trust.
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