It's become common for patients in the
intensive care unit (ICU), both children and adults, to receive probiotics.
Often, they are started at home to counteract diarrhea caused by antibiotics.
There is also interest in using probiotics proactively in the ICU. A large
multicenter clinical trial in Canada is testing whether probiotics would
prevent ventilator-associated pneumonia in adult ICU patients.
But a collaborative study published today in
Nature Medicine sounds a note of caution in using probiotics in the ICU. In a
small percentage of cases, the live bacteria in the probiotic formulations can
cause bloodstream infections.
Investigating
probiotic bacteremia
The investigation began when the Infection
Prevention and Control group at Boston Children's Hospital began noticing cases
of bacteremia in the ICU caused by Lactobacillus, a genus of bacteria commonly
found in probiotics. Thomas Sandora, MD, MPH, medical director of Infection
Prevention and Control, and pediatric infectious diseases physician Kelly
Flett, MD, were alarmed by the incidence—1.1 percent of patients receiving
probiotics in the ICU from 2009-2014. So they decided to do a case-control
study.
Sandora and Flett compared their six ICU
cases with another 16 patients in the ICU who were receiving probiotics but
didn't have bacteremia. The two groups were matched by type of underlying
illness and how long they had been receiving probiotics.
"We wanted to see if there were factors
we could identify clinically, so we could make recommendations about giving
probiotics in the ICU," says Flett, now at Novant Health Eastover
Pediatrics in North Carolina.
But no clear
risk factors emerged.
"We know from prior studies that certain
patients are at higher risk for infection from probiotics—usually those with
compromised immune systems, or problems with their intestinal tracts that would
allow probiotics to get into the bloodstream," says Sandora. "But
these patients did not have any of those risk factors. The only risk factor was
being critically ill in the ICU."
Genetic
forensics
That led to the study's next phase: a genomic
investigation. Through the hospital's Translational Research in Infection
Prevention in Pediatric Anesthesia and Critical Care Program, Gregory Priebe,
MD, in the Department of Anesthesiology, Critical Care and Pain Medicine, and
postdoctoral fellow Christina Merakou, Ph.D., collaborated with Patrick McGann,
Ph.D., and others at the Walter Reed Army Institute of Research. Using
whole-genome sequencing techniques, they demonstrated that the bacteria in the
patients' blood were an almost perfect match with those in the probiotic
capsules: a strain called Lactobacillus rhamnosus GG, or LGG.
"The high level of discrimination from
whole-genome sequencing was needed, since many Lactobacillus species are normal
colonizers of the GI tract," explains Priebe. "Other bacterial
fingerprinting methods such as pulsed-field gel electrophoresis don't offer
high enough discrimination to be sure two strains truly match."
The sequencing findings matched the
identification obtained in the hospital's Infectious Diseases Diagnostic
Laboratory.
"We used a research database on our
MALDI-TOF mass spectrometer to match the species identification of the patient
isolates to the organism in the probiotic capsules," explains Alexander
McAdam, MD, Ph.D., who directs that lab.
Single-base
resolution
The team then went a step further. With
collaborators Roy Kishony, Ph.D., and Idan Yelin, Ph.D., at Technion-Israel
Institute of Technology, they analyzed the bacterial DNA one base at a time,
comparing multiple isolates of LGG from both infected blood and the probiotic capsules.
"No one had ever checked base by
base," notes Merakou, who worked on the project for three years. "We
wanted to see if there were any new changes in the bacteria that might make
them more potent, or survive better in the blood. The technology allowed us to
go deep and see what was going on."
"We could determine the ancestry of the
bacteria and infer transmission from capsules to blood," adds Yelin,
"and at the same time identify the footprints of evolutionary pressures
acting upon these probiotics within the host."
Evolving
bacteria
The investigators found 11 positions in the
bacterial genome that varied among the blood isolates. They also showed that
some LGG bacteria in the probiotics, once established in the patient's GI
tract, developed a new mutation that made them antibiotic-resistant.
"We found one mutation affecting the
exact position where the antibiotic rifampin would bind to the bacteria,"
says Merakou. "Bacteria with the mutation become
antibiotic-resistant." Testing in McAdam's lab showed that these bacteria
were resistant to rifampin, but not to other antibiotics.
Some mutations were clearly coming from LGG
in different batches of probiotics, but others were found only in isolates from
patients' blood, suggesting they may have helped the bacteria enter or survive
within the bloodstream.
"The history of these bacteria is
written in the genome—how they move into the blood, what selection pressures
are acting on them, where they've been, where they're going," says
Kishony. "It's like a detective process. Much of the power comes from
crossing the genomic data with the patients' clinical data, such as the
antibiotics they are receiving."
Study
takeaways
Based on these forensics, the team suspects
that the bacteria entered the bloodstream from the GI tract, but it's also
possible that they entered via the patients' central lines. Five of the six
patients had central lines in place.
"Nurses have to open the capsules and
administer the bacteria through a feeding tube," explains Priebe.
"There was worry the bacteria could be contaminating the central line, and
from there get into the bloodstream."
To avoid this possibility, Boston Children's
has established new protocols requiring nurses to wear gloves before handling
probiotic capsules and then change gloves before administering the probiotics. Clinicians
now also cover the central line, if the patient has one, with a clean drape
before opening the capsules, and clean the surfaces where the probiotic was
prepared with a disinfectant. In 2016, the hospital decided to not allow the
use of probiotics containing LGG in ICU patients if they have a central line.
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