Overuse of broad-spectrum antibiotics such as ciprofloxacin allowed the drug-resistant bug to flourish, they reported in The Lancet Infectious Diseases, a medical journal.
When other bacteria in the gut are killed off by these antibiotics, the more deadly -- and resistant -- C. difficile has more room for rapid growth, they found.
Clostridium difficile, or C. diff, causes symptoms ranging from diarrhoea to life-threatening inflammation of the colon.
It typically affects older adults, and is associated with exposure to hospitals and health-care facilities.
More than half-a-million infections occur every year in the United States, including about 15,000 fatalities.
In Britain, the number of reported cases increased steadily from 1990 to 2007, when public concern prompted government action.
"Alarming increases in UK hospital infections and fatalities caused by C. difficile made headline news during the mid-2000s and led to accusations of serious failing in infection control," said co-author Derrick Cook, a professor at the University of Oxford.
Lack of hygiene and improper use of antibiotics were both suspected of playing a role.
A high-profile campaign to "deep clean" hospitals was undertaken, along with a newly restrictive policy on the use of so-called fluoroquinolone antibiotics in hospitals.
The campaign worked, with the number of infections in Britain dropping by 80 percent over the next 10 years.
But it remained unclear which of the two measures played the greater role.
To find out, Crook and colleagues analysed data on the number of C. difficile infections, and the quantity of antibiotics used, both in hospitals and by general practitioners.
The also sequenced the genomes of 4,000 different strains of the bacteria to figure out to which antibiotics they were resistant.
They concluded that the C. difficile epidemic was the unintended consequence of intensive use of the fluoroquinolones.
When this class of antibiotic was reduced, only the C. difficile bugs resistant to fluoroquinolones went away.
While hand hygiene to control the spread of disease remains essential, expensive deep cleaning on a routine basis was unnecessary, they said.
The findings are relevant to the United States, where prescription of this family of antibiotics "remains unrestricted," Crook said.
Other countries should take note as well, added co-author Mark Wilcox, a professor of microbiology at the University of Leeds.
"Bugs similar to C. difficile 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," he said in a statement.