People carry a community of microbes in and on our bodies, and they can have a powerful influence on our physiology in many ways. Probiotics, which are live microbes, are intended to improve human health, and they sometimes given to intensive care unit (ICU) patients of all ages. Antibiotics can cause diarrhea, and probiotics can help relieve it, and studies are researching whether they can prevent complications that arise in the ICU, like pneumonia. A new study reported in Nature Medicine has advised caution, however; probiotics may lead to bloodstream infections (bacteremia) in ICU patients.
At Boston Children's Hospital, the Infection Prevention and Control group began to find ICU patients with bacteremia caused by Lactobacillus bacteria, which are often found in probiotics. Pediatric infectious diseases physician Kelly Flett, M.D. and Thomas Sandora, M.D., M.P.H., medical director of Infection Prevention and Control found that from 2009 to 2014, 1.1 percent of ICU patients exposed to probiotics got bacteremia. These alarming findings led to further investigation.
The scientists matched two groups of ICU patients with similar illnesses that received probiotics for a certain period of time; in their groups, there were six cases of bacteremia and sixteen cases without the infection.
"We wanted to see if there were factors we could identify clinically, so we could make recommendations about giving probiotics in the ICU," explained Flett, now at Novant Health Eastover Pediatrics in North Carolina.
However, they could not pinpoint a risk factor. "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," said Sandora. "But these patients did not have any of those risk factors. The only risk factor was being critically ill in the ICU."
They turned to a genetic study to learn more and performed whole-genome sequencing that showed the infected patients' bloodstreams carried bacteria that were nearly identical, genetically, to those in the probiotic capsules. The offending microbe was identified as 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," explained a co-senior study author Gregory Priebe, M.D. "Other bacterial fingerprinting methods such as pulsed-field gel electrophoresis don't offer high enough discrimination to be sure two strains truly match."
The team confirmed the findings using a mass spectrometer, and then went further, assessing each base of the bacterial DNA.
"No one had ever checked base by base," noted a study co-first author and postdoctoral fellow Christina Merakou, Ph.D. "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 and at the same time identify the footprints of evolutionary pressures acting upon these probiotics within the host," added study co-first author Idan Yelin, Ph.D.
The bacteria isolated from the patient blood samples varied in eleven positions and showed that once the LGG bacteria arrived in the digestive tracts of the patients, they had acquired a mutation that gave them resistance to antibiotics.
"We found one mutation affecting the exact position where the antibiotic rifampin would bind to the bacteria," said Merakou. "Bacteria with the mutation become antibiotic-resistant."
Some of the probiotic LGG microbes contributed mutations, while others were only seen in the isolates from the blood samples; they may have helped the microbes get into the bloodstream and survive there. The scientists suggested that the bloodstream infections came from the gut, but they may have also come in through the lines feeding the patients.
"Nurses have to open the capsules and administer the bacteria through a feeding tube," explained Priebe. "There was worry the bacteria could be contaminating the central line, and from there get into the bloodstream."
Boston Children's Hospital has now instituted precautions to prevent that from happening, and in 2016, stopped giving probiotics to patients with a central line, a tube that sits in the patient's neck and can be used to administer drugs and fluids or to draw blood.