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HomeA FocusBeating C. Diff: A new treatment and restricting common antibiotic

Beating C. Diff: A new treatment and restricting common antibiotic

ClostridiumFocusRestricting the use of a common antibiotic was more important than a high profile 'deep clean' of hospitals in massively reducing antibiotic resistant Clostridium difficile, a major UK study finds. Meanwhile, a another large study found that new treatment for C.diff reduces recurrent infections by nearly 40%.

The study concluded that overuse of antibiotics like ciprofloxacin led to the outbreak of severe diarrhoea caused by Clostridium difficile (C.diff) that hit headlines from 2006 onwards. The outbreak was stopped by substantially reducing use of ciprofloxacin and related antibiotics.

Inappropriate use and widespread over prescribing of fluoroquinolone antibiotics such as ciprofloxacin in fact allowed C. diff bugs that were resistant to the drug to thrive, because non-resistant bugs in the gut were killed off by the antibiotic, leaving the way clear for rapid growth of resistant C. diff.

Concerns about hospital 'superbugs' which had become resistant to common antibiotics resulted in the announcement of a programme of “deep cleaning” and other infection control measures in the NHS in 2007.

The study, by the University of Leeds, University of Oxford and Public Health England found that cases of C. diff fell only when fluoroquinolone use was restricted and used in a more targeted way as one part of many efforts to control the outbreak.

The restriction of fluoroquinolones resulted in the disappearance in the vast majority of cases of the infections caused by the antibiotic-resistant C. diff, leading to around an 80% fall in the number of these infections in the UK (in Oxfordshire approximately 67% of C. diff bugs were antibiotic-resistant in September 2006, compared to only approximately 3% in February 2013).

In contrast, the smaller number of cases caused by C. diff bugs that were not resistant to fluoroquinolone antibiotics stayed the same. Incidence of these non-resistant bugs did not increase due to patients being given the antibiotic, and so were not affected when it was restricted.

At the same time, the number of bugs that were transmitted between people in hospitals did not change. This was despite the implementation of comprehensive infection prevention and control measures, like better handwashing and hospital cleaning in this case.

The study’s authors therefore conclude that ensuring antibiotics are used appropriately is the most important way to control the C. diff superbug. The authors note that it is important that good hand hygiene and infection control continues to be practiced to control the spread of other infections.

The study analysed data on the numbers of C. diff infections and amounts of antibiotics used in hospitals and by GPs in the UK. More than 4,000 C. diff bugs also underwent genetic analysis using a technique called whole genome sequencing, to work out which antibiotics each bug was resistant to.

Co-author Derrick Crook, professor of microbiology, University of Oxford said: “Alarming increases in UK hospital infections and fatalities caused by C. diff made headline news during the mid-2000s and led to accusations of serious failings in infection control.

“Emergency measures such as ‘deep cleaning’ and careful antibiotic prescribing were introduced and numbers of C. diff infections gradually fell by 80% but no-one was sure precisely why.

“Our study shows that the C. diff epidemic was an unintended consequence of intensive use of an antibiotic class, fluoroquinolones, and control was achieved by specifically reducing use of this antibiotic class, because only the C. diff bugs that were resistant to fluoroquinolones went away.

“Reducing the type of antibiotics like ciprofloxacin was, therefore, the best way of stopping this national epidemic of C. diff and routine, expensive deep cleaning was unnecessary. However it is important that good hand hygiene continues to be practiced to control the spread of other infections.

“These findings are of international importance because other regions such as North America, where fluoroquinolone prescribing remains unrestricted, still suffer from epidemic numbers of C. diff infections.”

Co-author Professor Mark Wilcox, professor of microbiology, University of Leeds, said: “Our results mean that we now understand much more about what really drove the UK epidemic of C. diff infection in the mid-2000s.

“Crucially, part of the reason why some C. diff strains cause so many infections is because they find a way to exploit modern medical practice.

"Similar C. diff bugs that affected the UK have spread around the world, and so it is plausible that targeted antibiotic control could help achieve large reductions in C. diff infections in other countries.”

Summary
Background: The control of Clostridium difficile infections is an international clinical challenge. The incidence of C difficile in England declined by roughly 80% after 2006, following the implementation of national control policies; we tested two hypotheses to investigate their role in this decline. First, if C difficile infection declines in England were driven by reductions in use of particular antibiotics, then incidence of C difficile infections caused by resistant isolates should decline faster than that caused by susceptible isolates across multiple genotypes. Second, if C difficile infection declines were driven by improvements in hospital infection control, then transmitted (secondary) cases should decline regardless of susceptibility.
Methods: Regional (Oxfordshire and Leeds, UK) and national data for the incidence of C difficile infections and antimicrobial prescribing data (1998–2014) were combined with whole genome sequences from 4045 national and international C difficile isolates. Genotype (multilocus sequence type) and fluoroquinolone susceptibility were determined from whole genome sequences. The incidence of C difficile infections caused by fluoroquinolone-resistant and fluoroquinolone-susceptible isolates was estimated with negative-binomial regression, overall and per genotype. Selection and transmission were investigated with phylogenetic analyses.
Findings: National fluoroquinolone and cephalosporin prescribing correlated highly with incidence of C difficile infections (cross-correlations >0·88), by contrast with total antibiotic prescribing (cross-correlations <0·59). Regionally, C difficile decline was driven by elimination of fluoroquinolone-resistant isolates (approximately 67% of Oxfordshire infections in September, 2006, falling to approximately 3% in February, 2013; annual incidence rate ratio 0·52, 95% CI 0·48–0·56 vs fluoroquinolone-susceptible isolates: 1·02, 0·97–1·08). C difficile infections caused by fluoroquinolone-resistant isolates declined in four distinct genotypes (p<0·01). The regions of phylogenies containing fluoroquinolone-resistant isolates were short-branched and geographically structured, consistent with selection and rapid transmission. The importance of fluoroquinolone restriction over infection control was shown by significant declines in inferred secondary (transmitted) cases caused by fluoroquinolone-resistant isolates with or without hospital contact (p<0·0001) versus no change in either group of cases caused by fluoroquinolone-susceptible isolates (p>0·2).
Interpretation: Restricting fluoroquinolone prescribing appears to explain the decline in incidence of C difficile infections, above other measures, in Oxfordshire and Leeds, England. Antimicrobial stewardship should be a central component of C difficile infection control programmes.

Authors
Kate E Dingle, Xavier Didelot, T Phuong Quan, David W Eyre, Nicole Stoesser, Tanya Golubchik, Rosalind M Harding, Daniel J Wilson, David Griffiths, Alison Vaughan, John M Finney, David H Wyllie, Sarah J Oakley, Warren N Fawley, Jane Freeman, Kirsti Morris, Jessica Martin, Philip Howard, Sherwood Gorbach, Ellie J C Goldstein, Diane M Citron, Susan Hopkins, Russell Hope, Alan P Johnson, Mark H Wilcox, Timothy E A Peto, A Sarah Walker, Derrick W Crook

 

A new treatment for C.diff reduces recurrent infections by nearly 40%, a large study has found.

C.diff, a bacterium that infects the bowel, is the most common cause of infectious diarrhoea in hospitalised patients. Recurrences are common after antibiotic treatment, are a cause of re-admissions to hospital, and in some cases can be fatal.

Now researchers have found that the addition of a drug called bezlotoxumab to standard antibiotic treatment can reduce the risk of a repeat infection by 37%. Bezlotoxumab is a human monocalonal antibody and works by neutralising a toxin produced by the C.diff bacteria that damages the gut wall.

Mark Wilcox, professor of microbiology at the University of Leeds, who led the study, said: “About one in four patients who have been treated with antibiotics for an initial C.diff infection will go on to have a repeat infection.

“These repeat infections are more difficult to treat, have more severe outcomes for the patient, and are associated with more hospitalisations. It is important to treat the first episodes of C. diff infection optimally, as each recurrence increases the chance of another episode even more.

“Fewer recurrent infections would mean less need to use antibiotics, fewer hospital admissions, reduced costs for the NHS and possibly a reduction in deaths.”

For the study, doctors conducted a double-blind, randomised, placebo-controlled trial involving 2,655 adults across over 300 hospitals in 30 countries worldwide. All the participants had primary or recurrent C.diff infections and were receiving standard-of-care antibiotics (metronidazole, vancomycin or fidaxomicin).

They were randomly assigned to receive infusions of: a single dose of (another human monocalonal antibody) actoxumab (10mg per kilogram of body weight); a single dose of bezlotoxumab (10mg per kilogram of body weight); a single dose of bezlotoxumab plus actotoxumab (10mg per kg of body weight); and a placebo (saline).

After initial cure of their C.diff, the patients were then followed up for 12 weeks to see how many developed another C.diff infection: in the actoxumab group, 26% developed another C.diff infection; in the bezlotoxumab group, 17% developed another C.diff infection; in the bezlotoxumab/actotoxumab group, 15% developed another C.diff infection: and in the placebo group, 27% developed another C.diff infection.

“Doctors should now consider which patients could best benefit from use of bezlotoxumab,” said Wilcox. “The studies showed that bezlotoxumab was particularly effective in those patients with risk factors for poor outcome, including older age, immunocompromise, and severe infection.”

Abstract
Background: Clostridium difficile is the most common cause of infectious diarrhea in hospitalized patients. Recurrences are common after antibiotic therapy. Actoxumab and bezlotoxumab are human monoclonal antibodies against C. difficile toxins A and B, respectively.
Methods: We conducted two double-blind, randomized, placebo-controlled, phase 3 trials, MODIFY I and MODIFY II, involving 2655 adults receiving oral standard-of-care antibiotics for primary or recurrent C. difficile infection. Participants received an infusion of bezlotoxumab (10 mg per kilogram of body weight), actoxumab plus bezlotoxumab (10 mg per kilogram each), or placebo; actoxumab alone (10 mg per kilogram) was given in MODIFY I but discontinued after a planned interim analysis. The primary end point was recurrent infection (new episode after initial clinical cure) within 12 weeks after infusion in the modified intention-to-treat population.
Results: In both trials, the rate of recurrent C. difficile infection was significantly lower with bezlotoxumab alone than with placebo (MODIFY I: 17% [67 of 386] vs. 28% [109 of 395]; adjusted difference, −10.1 percentage points; 95% confidence interval [CI], −15.9 to −4.3; P<0.001; MODIFY II: 16% [62 of 395] vs. 26% [97 of 378]; adjusted difference, −9.9 percentage points; 95% CI, −15.5 to −4.3; P<0.001) and was significantly lower with actoxumab plus bezlotoxumab than with placebo (MODIFY I: 16% [61 of 383] vs. 28% [109 of 395]; adjusted difference, −11.6 percentage points; 95% CI, −17.4 to −5.9; P<0.001; MODIFY II: 15% [58 of 390] vs. 26% [97 of 378]; adjusted difference, −10.7 percentage points; 95% CI, −16.4 to −5.1; P<0.001). In prespecified subgroup analyses (combined data set), rates of recurrent infection were lower in both groups that received bezlotoxumab than in the placebo group in subpopulations at high risk for recurrent infection or for an adverse outcome. The rates of initial clinical cure were 80% with bezlotoxumab alone, 73% with actoxumab plus bezlotoxumab, and 80% with placebo; the rates of sustained cure (initial clinical cure without recurrent infection in 12 weeks) were 64%, 58%, and 54%, respectively. The rates of adverse events were similar among these groups; the most common events were diarrhea and nausea.
Conclusions: Among participants receiving antibiotic treatment for primary or recurrent C. difficile infection, bezlotoxumab was associated with a substantially lower rate of recurrent infection than placebo and had a safety profile similar to that of placebo. The addition of actoxumab did not improve efficacy.

Authors
Mark H Wilcox, Dale N. Gerding., Ian R Poxton, Ciaran Kelly, Richard Nathan, Thomas Birch, Oliver A Cornely, Galia Rahav, Emilio Bouza, Christine Lee, Grant Jenkin, Werner Jensen, You-Sun Kim, Junichi Yoshida, Lori Gabryelski, Alison Pedley, Karen Eves, Robert Tipping, Dalya Guris, Nicholas Kartsonis, Mary-Beth Dorr

[link url="http://www.leeds.ac.uk/news/article/3978/overuse_of_antibiotics_the_main_cause_of_cdiff_epidemic"]University of Leeds material[/link]
[link url="http://www.thelancet.com/journals/laninf/article/PIIS1473-3099(16)30514-X/fulltext"]The Lancet Infectious Diseases article summary[/link]
[link url="http://www.leeds.ac.uk/news/article/3980/new_cdiff_treatment_reduces_recurrent_infections_by_40"]University of Leeds material[/link]
[link url="http://www.nejm.org/doi/full/10.1056/NEJMoa1602615?query=featured_homehttp://www.nejm.org/doi/full/10.1056/NEJMoa1602615?query=featured_home"]New England Journal of Medicine abstract[/link]

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