For the past few years, physicians
in hospitals from Sweden to Sherbrooke, QC have been
observing what appears to be a trend towards greater
virulence of Clostridium difficile. At last,
it seems, we know why this disease is becoming more
deadly.
Dr Michel Warny and colleagues
make a compelling case in the most recent edition of
The Lancet that the culprit is a toxinotype III strain
called NAP1/027, found in only 2% to 3% of hospital
isolates. Though still far less common than toxinotype
0 strains, the newer strain has undergone genetic changes
that appear to explain C difficile's increasingly
lethal toll.
In the 1990s, C difficile
killed only about one patient in 25 of those stricken.
A study soon to be published in the Canadian Medical
Association Journal will report a one-year mortality
rate of one in six for Quebec during 2003 and 2004.
Dr Jacques Pepin of the Centre Hospitalier Universitaire
de Sherbrooke used the experience of his own hospital
to extrapolate a total of 2000 deaths province-wide.
That number is far higher than any previous estimate,
and is hotly contested by the Public Health Institute
of Quebec.
TRACKING
THE KILLS
Dr Pepin insists that the Sherbrooke experience is not
an anomaly in Quebec. "The infection traveled from Montreal
to Sherbrooke, and not the other way around. If anything
they have a higher incidence in Montreal than we do
here, where up to three-quarters of all isolates are
of the epidemic strain, with about two-thirds."
But while the death toll remains
contentious, all experts agree that the outbreak strain
killed 100 patients in Sherbrooke despite extraordinary
efforts to halt it.
C difficile kills by producing
two toxic proteins, known as toxin A and toxin B. In
NAP1/027, a gene that once down-regulated toxin production
has been deleted. That deletion has caused toxin A production
to multiply to 16 times the level of the toxinotype
0 strains that have, until now, accounted for about
80% of hospital isolates. Production of toxin B, which
attacks the colon's epithelium even more aggressively
than toxin A, is increased 23-fold.
These results are in vitro and
we don't know if we can translate them to the bowel,"
says Dr. Warny. "But we do have unpublished findings
that suggest mortality among patients is about three
times higher."
AT
GREATER RISK
Patients who have taken cephalosporins, clindamycin,
and macrolides are already known to be at greater risk
of C difficile infection. Fluoroquinolones, and
especially ciprofloxacin, appear to be particularly
implicated in NAP1/027 infection. At greatest risk are
patients who develop fluoroquinolone resistance, now
the most-prescribed antibiotics in many developed countries.
In addition to being very virulent,
NAP1/027 is also highly transmissible. Researchers speculate
that this may be because it causes such severe diarrhea,
giving the spores more opportunities to find new hosts.
FULL
ISOLATION?
"This is just another message, as if one were needed,
that we need to modernize our hospitals and change the
way we handle patients," says Dr. Andrew Simor, an infectious
disease specialist who heads the Microbiology Department
at Toronto's Sunnybrook and Women's Hospital.
"The patient profile today is utterly
different from what it was 50 years ago. Just to be
admitted today you pretty much have to be critically
ill. We should really be treating everyone we admit
as a high-risk patient who needs to be isolated. "
CAN'T
DO IT?
Dr Warny, author of The Lancet study, says it
isn't realistic to hope that hospitals can eradicate
such a tenacious epidemic, although they should keep
on trying to improve sanitation and move away from broad-spectrum
antibiotics.
Dr Warny's company Acambis is currently
testing a vaccine on healthy human subjects in the US.
It has already shown promise in treating infection in
animal models. If the vaccine proves safe and effective
in humans, the next step will be to decide who should
receive it (Everyone checking into a hospital? Everyone
taking quinolones? Everyone over 65?) .
VACCINE
HOPE
In the long run, Dr Pepin says he is pinning his greatest
hopes on a vaccine. "The tetanus vaccine was based on
the same idea, of altering a toxin so that it is no
longer pathogenic but is still immunogenic. And it's
worked for the past 60, 70 years."
For the time being, the only weapon
physicians really have to fight C difficile is
the one that helped create the epidemic in the first
place: antibiotics.
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