Known as mrCDI (multiple recurring C. difficile infections), they are the most difficult to treat and are rapidly becoming more common, say scientists.
In the US between 2001 and 2012 the annual rate rose by almost 200 per cent more than four times the increase in 'ordinary' C. diff.
The bug, which can kill elderly patients, most commonly affects those who have recently been treated with antibiotics.
The precise reasons for the sharp rise in mrCDI's incidence is so far unknown but adds strain to healthcare systems with an urgent need for new treatments.
The most promising is a therapy called FMT (faecal microbiota transplantation) the infusion of beneficial intestinal bacteria into patients.
It has shown good results in small studies in the war on C. diff but hasn't yet been thoroughly evaluated.
Professor James Lewis, of Pennsylvania University, said: "The increasing incidence of C. difficile being treated with multiple courses of antibiotics signals rising demand for faecal microbiota transplantation in the United States.
"While we know faecal microbiota transplantation is generally safe and effective in the short term, we need to establish the long term safety of this procedure."
Loss of appetite, nausea
C.diff is a bacterium that causes inflammation of the colon, a condition called colitis. Symptoms include diarrhoea, fever, loss of appetite, nausea and abdominal pain.
Recurrent C.diff, a bout within 90 days of the last, is a major problem with the risk of contracting it again at 50-60 per cent after three or more infections.
The bacteria are found in faeces, and people can become infected if they touch items or surfaces that are contaminated and then touch their mouths or mucous membranes.
C. diff afflicts half a million Americans a year causing tens of thousands of deaths and costing the nation's healthcare system an estimated $5 billion.
The study published in the Annals of Internal Medicine identified the alarming trend by analysing a nationwide health insurance database with the records of more than 40 million US patients.
Cases of C. diff were considered to have multiple recurrences when doctors treated them with at least three closely spaced courses of antibiotics.
According to the analysis, the incidence of C diff rose by about 43 percent over the study period, compared to 189 percent for mrCDI.
Older females more susceptible
The latter group were more likely to be older with an average age of 56, seven years more than the former's 49 and were more likely to be female (64 per cent vs. 59 percent.
They were also more likely to have been exposed previously to medications such as corticosteroids, heartburn drugs known as PPIs (proton-pump inhibitors) and antibiotics.
The rapid rise in the incidence of mrCDI may be due in part to Americans' increasing use of such drugs. But Prof Lewis said other causes are also likely.
He said: "An additional driver of this rise in incidence could be the recent emergence of new strains of C. difficile, such as NAP1, which has been shown to be a risk factor for recurrent CDI."
C.diff is notorious for spreading among vulnerable patients within hospitals and can lead to fatal blood infections (sepsis) - especially among the elderly.
The antibiotics metronidazole, vancomycin, and fidoxamicin are commonly used to treat CDI, but recurrence after initial treatment happens in roughly a third of cases.
Long used in veterinary medicine, FMT is an alternative to antibiotics and involves infusions of foecal matter from healthy intestines.
The aim is to help restore a normal gut bacteria population in the patient and thereby discourage C. diff growth.
A small study in 2013 found a single FMT infusion cleared up diarrhoea in 81 percent of the recurrent-CDI patients who received it. On the other hand the standard antibiotic vancomycin worked for just 31 percent.
But Prof Lewis said despite such promising results more needs to be known about FMT's long-term safety - and the fast-rising incidence of mrCDI underscores this need.
The American Gastroenterological Association recently set up a formal registry for doctors to report their results with FMT procedures.
Prof Lewis said: "It's a way in which practitioners who are performing faecal microbiota transplantation can contribute data to help answer these critical questions."