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Antibiotics can help fragile premature babies survive. But they may have a cost later in life.

Jesse S. Jones/University of Florida

Too many antibiotics can give preemies a lifetime of ill health

Should she change the dose of steroids? Administer a diuretic? Remove the feeding tube? Rachel Greenberg makes hundreds of crucial decisions while shuffling through the dimly lit bays of the neonatal intensive care unit (NICU) at Duke University Medical Center in Durham, North Carolina. As she checks on the little ones entrusted to her care, some babies fuss in open cribs beneath mobiles emitting soothing tones; the smallest, weighing less than half a kilogram, slumber in cases of clear plastic. In the corners, computer monitors silently shout messages such as "Wash your hands!"

Near the end of Greenberg's rounds, the young neonatologist visits one of the newest arrivals, a baby girl with mahogany skin and wisps of black hair, recently transferred from a community hospital. She was born 4 weeks too early, and though she's faring better than most in the NICU, a note in her chart concerns Greenberg. Doctors at the community hospital had given the baby antibiotics without testing for an infection. Greenberg wonders whether the drugs were necessary. She had run a blood culture herself and found no bacteria. Maybe the baby never had an infection. Or maybe she had, and the antibiotics were working. With no way to know, Greenberg continues the medication.

Like that baby, the vast majority of the nearly half-million infants born prematurely in the United States are given antibiotics, even without evidence of infection. Many preemies are kept on the drugs after blood tests say they are not sick. Yet that practice, once considered the best way to protect a hospital's most vulnerable patients, is now being challenged. "We're beginning to recognize that the risk of giving that antibiotic may actually outweigh the benefit," says Josef Neu, a neonatologist at the University of Florida in Gainesville.

Some studies suggest that even while helping fight certain infections, those drugs may encourage others by wiping out an infant's developing gut microbiome—those trillions of resident microbes with functions as diverse as synthesizing vitamins and bolstering our immune systems. By disrupting that microbial ecosystem, blanket antibiotic dosing of babies, particularly preemies, may promote a host of problems later in life, such as asthma and obesity. And recent research indicates that long after preemies leave the NICU, they can harbor many antibiotic-resistant microorganisms, potentially endangering not only themselves, but also the wider population.

In all corners of medicine, doctors are waking up to the dangers of antibiotic overuse. But change is coming slowly to the NICU. Another message that pops up on the monitors at Duke is: "Antibiotics are not always the answer!" Yet many neonatologists hesitate to alter their habits, unable to shake the fear that a baby may die on their watch. "We are working to change our perception … to fight the belief that antibiotics are always the safe thing to do," Greenberg says.

Neu hopes to provide hard evidence with a small clinical trial: A random selection of premature infants who would have been given antibiotics automatically will instead be placed in a nontreatment control group. For 2 years, his team will track the microbiomes and health of the preemies. Some of Neu's colleagues feel uneasy about withholding antibiotics, but he says answers are needed. "What can we do to use these antibiotics more intelligently? This is, I think, one of our biggest conundrums in neonatal intensive care right now."

Costly successes

Today, babies born as early as 28 weeks routinely survive, as do more than half of those born at 24 weeks (although often with significant disabilities). Much of the credit goes to antibiotics, which have thwarted infections such as sepsis and group B strep that a preemie's immature immune system could not have fought on its own. Those successes spurred a steady increase in routine antibiotic use in the NICU. At last count, three of the top four drugs prescribed in the NICU were antibiotics.

Over time, however, scientists began noticing that antibiotics can increase babies' risk of the very afflictions the drugs aim to protect against—such as fungal infections, late-onset sepsis, and a deadly intestinal disorder called necrotizing enterocolitis. In a seminal 2009 study in Pediatrics, for example, Greenberg's colleague Michael Cotten showed that each additional day of antibiotics significantly increased the odds that a preemie would develop necrotizing enterocolitis or die.

Researchers are still debating when the first microbes colonize us—in utero or during birth—but Greenberg and many others worry that early use of antibiotics in infants disrupts the establishment of those indispensable residents. The gut microbiome is practically an organ unto itself, weighing about as much as the liver. It is thought to play a critical role in priming the immune system, and it produces just as many neurotransmitters as the human brain. Genetic and environmental factors, including antibiotics, shape its makeup early in life. Then, around age 3, a quasi-stability sets in and we are "stuck with that architecture," says Gautam Dantas, a microbiologist at Washington University in St. Louis, Missouri.

An early barrage of antibiotics

Premature babies often receive multiple medications. Three of the four most prescribed are antibiotics (red), which are routinely given even when no infection is present.

9. Midazolam 10. Calfactant 7. Fentanyl 8. Dopamine 5. Beractant 6. Furosemide 4. Vancomycin 3. Caffeine Antibiotic that treats gram-negative bacteria 1. Ampicillin 2. Gentamicin Broad-spectrum antibiotic that treats bacterial infections Antibiotic that treats gram-positive bacteria Stimulant that treats apnea and aids breathing Diuretic that helps reduce extra fluid in the body Increases blood pressure, and helps heart beat stronger Strong, short- acting narcotic that relieves pain Surfactant that helps lungs function normally Sedative that helps reduce stress Surfactant that helps lungs function normally

(Graphic) K. Sutliff/Science; (Data) E. M. Hsieh et al., American Journal of Perinatology 9, 811 (2014)

Dantas recently began tracing those dynamics in premature babies, whose microbiomes are just being established. In stool samples of premature infants from the St. Louis Children's Hospital, he was shocked to discover that every child had been exposed to antibiotics. As a result, none of the samples could serve as controls. Instead, he compared stool samples from preemies who had been exposed to antibiotics for just a few days to stool from those exposed for a few months. He found that babies on long-term antibiotics had only a 10th of the bacterial diversity. In addition, their dominant denizens were a "who's-who list of bad gut pathogens," he says. "Our speculation is that because of all the high antibiotic pressure, those are the only bugs that can survive, and they probably are coming in from surfaces in the NICU."

Over the past 2 years, Dantas has traced what happened to those impoverished microbiomes after the babies left the hospital. He showed that at first, the preemies' microbiomes remained stunted. But by 4 to 6 months of age they had become just as diverse as those of full-term babies. Dantas speculates, though, that the preemies "may never truly catch up" because they lacked a normal microbial complement at times when they reached key developmental milestones.

That legacy might explain a growing number of suggestive links between early use of antibiotics and disorders such as asthma, autoimmune disease, and obesity. For example, in a retrospective analysis of medical records from 64,580 children, those exposed to antibiotics in their first 24 months were at higher risk of early childhood obesity.

Dantas found another disturbing consequence when he examined the microbiomes of 2-year-olds who had been exposed to antibiotics in the NICU: microbes resistant to every antibiotic he tested, even colistin, one of the last-resort drugs. Their guts had basically become a breeding ground for antibiotic-resistant microorganisms. "The picture may not be completely grim, but it's not rosy for sure," he says. "I understand there's a risk of infection, but I just haven't seen compelling data or evidence that showed a clear benefit of those drugs."

Changing a mindset

Many scientists think the only way to understand the real impact of antibiotics on preemies is to stop automatically giving them when an infant shows up in the NICU. That's what Neu's trial aims to do. At first, he says, the university's institutional review board balked at his proposal for a randomized control trial, questioning whether he could get enough parents to consent to withholding medication from their premature babies. But he says parents are generally receptive to the study once they understand that the mom or the baby will definitely receive antibiotics if either is at very high risk of infection.

Neu and his team plan to enroll 150 premature infants. However, the study, launched last year, has had a slow start. Physicians, not parents, have proved to be the biggest roadblock, Neu says. Doctors taking part in the study often put an infant on antibiotics at the first sign of illness, even if the baby had been randomized to the control group. Some colleagues have told him they can't worry about a later risk of asthma or obesity when their patient might not make it out of the NICU alive.

A better test for infection could help change that mindset. Blood cultures aren't foolproof and can take 24 to 48 hours. By then a preemie is likely to be on antibiotics already. "We don't have great tests beyond the blood culture to tell us who's got an infection," Cotten says. "And when a kid is falling apart over days in front of you, you worry that infection is the cause and you worry that your blood culture wasn't sensitive enough … so you feel like you have to treat."

Neonatologist Karen Puopolo of the Children's Hospital of Philadelphia in Pennsylvania recently developed a fast way to screen for serious bacterial infections in full-term infants. Her algorithm is based on gestational age; maternal risk factors, such as when the amniotic sac ruptured; and the infant's clinical exam. According to a recent study in multiple hospitals, Puopolo's sepsis calculator cut the percentage of babies given antibiotics in half, and hundreds of other hospitals are now using it. But she says developing a similar tool for preemies has proved tricky because the standard risk factors would predict that most of them have an infection.

However, Puopolo discovered one factor that could distinguish between preemies at high and low risk of infection: whether they were delivered vaginally or by cesarean (C-section). Infants delivered early because of maternal health problems—such as preeclampsia, cancer, or severe kidney disease—account for about a third of all preterm births. Those babies are typically born by "elective" C-section, which doesn't expose them to risk of infection from bacteria in the birth canal. Using data from 5300 premature babies in the NICU at Brigham and Women's Hospital in Boston, Puopolo showed that those born via C-section had one-twelfth the incidence of sepsis. "That is a distinction that neonatologists know, but they haven't been using that knowledge in how they treat babies," Puopolo says. Last year, she worked with Cotten to look at the use of antibiotics in 15,000 late preterm and full-term babies. Many low-risk babies—defined primarily as those born through C-section—were not only put on antibiotics, but also kept on them for more than a week.

Still, the trend may be changing. Over the past decade, Cotten and Greenberg have tracked antibiotic use and infant health at Duke and 12 other NICUs. In forthcoming research, they found that the number of premature babies kept on antibiotics after a negative blood culture dropped from 50% in 2008 to 36% in 2014, the most recent year for which such data are available. That drop did not come with an increase in death or infection; if anything, Greenberg says, it may have improved outcomes.

Doctors are not the only ones starting to pay attention. Over the past year, Cotten has had several families ask him whether putting their preemie on antibiotics is a good idea—a question he hadn't heard in almost 30 years on the job. "The public is starting to ask, parents are starting to ask," he says. "I think … the message is getting out."