Dramatic declines in Clostridium difficile infections in English hospitals appear to result from restrictions in a commonly used antibiotic, according to a study yesterday in The Lancet.
The study, led by researchers from Oxford University and Public Health England, set out to determine what's behind an 80% decline in C difficile incidence in England after 2006, when the country was in the midst of a series of outbreaks in English hospitals that led to an overhaul of infection prevention policies. Those policies were implemented in 2007, a year in which more than 50,000 people contracted C difficile in England, and several hundred died.
C difficile is a bacterium that causes inflammation of the colon and severe diarrhea. Although it is a natural part of the gut microbiome, infections commonly occur in healthcare settings among older patients being treated with antibiotics, which can wipe out the bacteria that help keep C difficile in check.
The outbreaks in England were part of a steady increase in incidence that was mainly fueled by a virulent strain of C difficile that emerged in the early 2000s—known as ribotype 027/BI/NAP1—and affected people of all ages, both in hospitals and in the community. The strain causes more-severe infections by producing more toxins.
Poor hygiene a factor?
At the height of the outbreaks, explains Oxford University microbiologist and lead study author Derrick Crook, MBBCh, the conventional wisdom was that "dirty hospitals" were behind both the spread of C difficile infections and a simultaneous rise in MRSA infections. "The general public's view was that transmission was occurring in hospitals because of poor hygiene," Crook told CIDRAP News.
Public and political outcry over poor hygiene and infection control led to the ousting of several National Health Service (NHS) executives. A "deep cleaning" program, in which wards at hospitals across the country were cleared out so staff could wash walls and dismantle and clean beds, was instituted.
Other elements of the English government's strategy to reduce C difficile infections included avoiding cephalosporin antibiotics (to which C difficile is almost universally resistant) and clindamycin, minimizing the use of fluoroquinolones , carbapenems, and aminopenicillin, and improving infection prevention and control strategies. Patient isolation, enhanced environmental cleaning, and renewed emphasis on hand washing were a core feature of these efforts.
Since peaking in 2007, C difficile incidence in England has steadily and dramatically declined, fueling a perception that deep cleaning and other efforts to improve hygiene at hospitals were to blame.
But Crook, who was a hospital epidemiologist at the time of the outbreaks, was skeptical that poor hygiene was the real culprit. So he and his colleagues set out to try to understand what fueled the steady rise in C difficile incidence.
In their initial investigation, published in the New England Journal of Medicine in 2013, they performed whole-genome sequencing of C difficile isolates in healthcare settings in Oxfordshire. In that study, they found that only some of the infections had been acquired via transmission from other infected patients, and they were not able to identify any substantial transmission networks, which would have indicated that the infections were spreading from person to person, aided by poor infection control. They concluded that more than 80% of the C difficile cases had been acquired from a large reservoir of bacteria, and not from other cases.
"That really got us thinking," Crook said.
And since they knew that C difficile type 027 was also resistant to fluoroquinolones, they hypothesized that fluoroquinolone resistance might be prominent in other strains that had been causing disease in England.
Role of fluoroquinolone resistance
The current study, in which whole-genome sequencing was performed on more than 4,000 isolates from hospitals in Oxfordshire and Leeds to determine antibiotic susceptibility, supports that hypothesis. The findings indicate that the overall reduction in C difficile infections in those two communities is largely the result of a significant decline in isolates from four genetically distinct strains—including 027—that were all resistant to fluoroquinolones. By contrast, the incidence of infections caused by fluoroquinolone-susceptible strains remained unchanged.
Furthermore, Crook explained, when the researchers analyzed isolates for evidence of person-to-person transmission, they found that the incidence of transmitted cases fell only among cases caused by the four strains of fluoroquinolone-resistant C difficile. There was no change in transmitted cases caused by fluoroquinolone-susceptible isolates.
"The change in incidence that we've seen was entirely explained by the disappearance of the quinolone-resistant lineages," Crook said. "And there was no change in the quinolone-susceptible populations."
And, as an analysis of national antibiotic prescribing data from 1998 to 2013 showed, the disappearance of fluoroquinolone-resistant strains occurred alongside significant reductions in fluoroquinolone use in English hospitals and in the community after 2006.
All this suggests that reducing the selective pressure fueled by fluoroquinolones played a much larger role in containing C difficile incidence than did deep cleaning, cutting other antibiotics, and improving infection control measures. If those other measures did have an impact, Crook explained, it would have been reflected by universal reductions in other C difficile strains.
Cutting fluoroquinolone use
Given the findings, Crook said that the "irresistible inference" is that cutting fluoroquinolone use, as part of a wider antimicrobial stewardship policy, could lead to declines in C difficile incidence in the United States and elsewhere. "It would be desirable to do…and one would expect it would have an effect," Crook said.
C difficile is considered an urgent threat by US health officials. The Centers for Disease Control and Prevention estimates that C difficile causes nearly 250,000 US hospitalization a year and 14,000 deaths. From 2000 to 2007, C difficile–related deaths increased by 400%, in part because of the spread of the 027 strain.
But Crook also acknowledged that reducing fluoroquinolone use by 50%—as has been done in England—will be very difficult to do in the United States, since fluoroquinolones are used widely in the US healthcare system.
Brad Spellberg, MD, an infectious disease specialist at University of Southern California, agrees.
"We massively overuse quinolones in the US, and, unfortunately, national guidelines have helped propagate the overuse by promoting these drugs as first line for diseases where other drugs can also be used," Spellberg said.
Spellberg said fluoroquinolones should be reserved for broad-spectrum gram-negative infections, which tend to be more resistant and harmful to humans, and should be used for less harmful gram-positive infections only when other options can't be used.
"This should become a focus of change in national guidelines, in [Food and Drug Administration] approving and labeling, and in payer, regulator, and professional expected practice," Spellberg added.
See also:
Jan 24 Lancet Infect Dis study
