Imagine a pathogen that infects completely
healthy people and can cause blindness in one day and flesh-eating
infections, brain abscesses and death in just a few days. Now imagine
that this pathogen is also resistant to all antibiotics.
This is the nightmare scenario that obsesses Thomas A. Russo, MD,
professor of medicine in the Jacobs School of Medicine and Biomedical
Sciences at the University at Buffalo. Since seeing his first case in
Buffalo seven years ago, he has been investigating hypervirulent
Klebsiella pneumoniae, a rare but increasingly common strain of K. pneumoniae.
There is no accurate method for distinguishing between the hypervirulent strain from the classical strain of K. pneumoniae, which is most often seen in the Western hemisphere, is less virulent and usually causes infections in hospital settings.
Now Russo, who heads the Division of Infectious Diseases in the UB
Department of Medicine, and his colleagues have discovered several
biomarkers that can accurately identify hypervirulent K. pneumoniae. The research was published in late June in the Journal of Clinical Microbiology.
In a commentary paper the journal published on June 27, authors from
the Fujita Health University School of Medicine in Japan and the
University of Pittsburgh School of Medicine noted that the UB research
is "a major step forward" in developing a consensus definition of the
hypervirulent strain and in designing international studies to reveal
more about its epidemiology and clinical presentation.
"Presently, there is no commercially available test to accurately
distinguish classical and hypervirulent strains," said Russo. "This
research provides a clear roadmap as to how a company can develop such a
test for use in clinical laboratories. It's sorely needed."
Russo added that a definitive diagnostic test would not only optimize
patient care but would also allow researchers to perform epidemiologic
surveillance to track how frequently the hypervirulent strain causes
infection and how frequently it acquires antimicrobial resistance.
While the assumption is that the pathogen spreads from person to
person through food and water, the mode of transmission is unknown.
No way to tell the difference
Russo explains that both strains of K. pneumoniae can be
deadly, but the classical strain is more likely to infect patients with
underlying disease, or who are immune-compromised and hospitalized.
By contrast, the hypervirulent strain can infect healthy, young
people in the community, causing sudden, life-threatening complications,
ranging from liver or brain abscesses to flesh-eating infections. While
it's currently less likely to be antibiotic resistant, these strains
continue to evolve. Classical strains are more likely to be
antimicrobial resistant.
"What's increasingly concerning is the growing number of reports that describe strains of hypervirulent K. pneumoniae that are antimicrobial resistant," said Russo. "A bug that's both hypervirulent and challenging to treat is a bad combination."
An antimicrobial-resistant hypervirulent strain can develop in one of
two ways, he explained: either by acquiring antimicrobial-resistance
genes, or when an antimicrobial-resistant classical strain acquires
hypervirulence.
"The latter mechanism is what caused the deaths of five patients in
the intensive care unit of a hospital in Hangzhou, China, which was
reported early this year," Russo said.
Since clinical laboratories have no test to detect the hypervirulent
strain, it's difficult, if not impossible, to properly diagnose it. The
so-called string test, currently used in some cases to distinguish the
classical and hypervirulent strains, is not consistently accurate,
according to the UB research. It's especially problematic, Russo said,
in North America and Europe, where there is a low prevalence of the
hypervirulent strain.
"Many clinicians are unaware of the hypervirulent strain," said
Russo. "And because there's no diagnostic test, the clinical lab can't
give them a heads up."
Finding the source of hypervirulence
Russo and his co-authors knew that the hypervirulence of K. pneumoniae
is largely due to genes located on a large virulence plasmid, DNA that
is independent from the chromosome. They hypothesized that some of these
genes, including those producing iron-acqusition molecules called
siderophores, might be good biomarkers. This proved to be the case.
They also found that higher concentrations of siderophores predicted
hypervirulence. They then validated the identified biomarkers in a mouse
infection model.
"The advantage of identifying these genetic biomarkers is that they
can be developed into rapid nucleic acid tests, and if approved by the
Food and Drug Administration, would then provide clinicians with an
accurate method to quickly determine if a patient is suffering from an
infection due to the classical or hypervirulent strain," Russo
explained.
He added that such a test will not only benefit patients and possibly
save lives, but will also prove critical in learning more about
hypervirulent K. pneumoniae.
"For example, we don't know the frequency of infection by hypervirulent K. pneumoniae
in different parts of the world," he said. "We know it infects all
ethnic groups, but so far it's been described most often in Asians,
particularly in Asian Pacific Rim countries. Is that because
hypervirulent K. pneumoniae is more commonly acquired in that
part of the world but doesn't necessarily result in infection, or
because some Asian populations are, for some reason, more susceptible to
it? Now we can begin to study those kinds of epidemiological
questions."
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