Dismantling the Resistance

Lifesaving when you need them, antibiotics are not benign, and their overuse can have deadly consequences, note Johns Hopkins researchers, who are “selling stewardship” here and across the country.

A woman wearing a white uniform and a red hard hat jackhammers a cracked, giant pill.

Illustration by Edmon de Haro

For years, experts have warned that the overuse of antibiotics helps bacteria learn to defeat these medications, turning once readily treatable infections dangerous, even deadly. Yet, research points to other urgent reasons to curb these prescriptions. 

In fighting bacterial infections, antibiotics bring on harmful side effects, and studies are uncovering evidence of long-term problems they may cause. These drugs decimate not just the pathogens but also the many helpful bacteria that inhabit our guts, and so boost risk for serious, often chronic conditions, including allergies, asthma, inflammatory bowel disease, diabetes, obesity and cancer.

“We’re much more aware now than we used to be that antibiotics are not benign,” says Johns Hopkins’ Pranita Tamma, associate professor of pediatrics.

Pranita TammaPranita Tamma

Tamma and other researchers at Johns Hopkins are exploring these issues and working to better treat bacterial infections. Truly addressing the problems that accompany antibiotics means limiting the use of these drugs only to the most specific, shortest courses in cases that truly warrant them, she and other experts say.

This approach requires a shift in mindset and changes in behavior for both those who prescribe these medications and those who take them. Tamma; Sara Cosgrove, director of The Johns Hopkins Hospital’s program in antimicrobial stewardship; and their colleagues are spearheading efforts to enact these changes both at Johns Hopkins and around the country — with the goal of better preserving the benefits of these medications while mitigating their harm.

Disrupting the Microbiome

“The crux of antibiotics is if you’re really sick and you have an infection, you need them,” says Cynthia Sears, the Bloomberg-Kimmel Professor of Cancer Immunotherapy and an infectious disease specialist. However, she says, “they’re a double-edged sword.”

Her own research has brough to light some of the harm antibiotics can cause to the microbes that normally inhabit our bodies and, potentially, to our own health.

The human body is coated in microbes, many of which support physiological processes. These good bugs are most abundant in our guts. Within them, an immense number of nonhuman cells aid in digestion and nutrient absorption, help to control the immune and nervous systems, and assist in maintaining a healthy intestinal barrier, which separates the interior of the body from the foreign material passing through the intestines.

Antibiotics, particularly those with broad spectrums intended to wipe out many types of bacteria, don’t discriminate friend from foe.

“There are inevitably off-target effects, where bugs that are not supposed to be killed in fact get killed,” Sears says. “You unequivocally disrupt the microbiome with any antibiotic you take.”

Increasingly, research is linking disturbances to the microbiome caused by antibiotics with a growing list of conditions that includes cancer and metabolic and immunological diseases.

A study Sears and her colleagues described in Gut indicates it may not take many prescriptions to increase the long-term risk for one such disease, colon cancer. When the team examined medical records in the United Kingdom, they found that limited exposure to oral antibiotics — 15 nonconsecutive days throughout life — correlated with an increased risk of colon cancer more than 10 years later.

Cynthia SearsCynthia Sears

Under normal circumstances, gut microbes have established niches, or positions, within a stable community. An antibiotic “upsets the applecart,” Sears says, by eliminating many of the beneficial inhabitants and favoring more harmful ones. In the short term, this dynamic can lead to new infections, including by the notorious pathogen Clostridioides difficile, which causes severe, even fatal diarrhea.

As time passes after the assault of an antibiotic, the microbial communities reassemble, but not always completely, according to Sears. And this can be dangerous, given that gut microbes produce their own molecules that influence health, for good and for bad. For example, when certain bacteria digest dietary fiber, like that found in legumes and whole grains, they produce a short-chain fatty acid known as butyrate. This molecule benefits intestinal health in several ways, including by supporting the intestinal barrier, disruptions to which occur in inflammatory bowel disorders. Meanwhile, Escherichia coli that possess the enzyme polyketide synthase produce an ephemeral molecule known as colibactin, which damages DNA. Colibactin likely contributes to colon cancer, although the magnitude of its role remains unclear.

 “The bugs may be there, but is the balance the same? Not necessarily,” Sears says, noting these changes may give the pathogenic microbes more influence. “When you take that impact over decades, that may contribute to chronic disease. That’s our hypothesis.”

Sears is continuing to examine the connection between gut microbes and colon cancer by focusing on several species of bacteria, including C. difficile and E. coli. Her lab also studies how gut microbes influence patients’ response to immunotherapy, which seeks to augment the immune system’s ability to fight cancer. Members of her group, including Fyza Shaikh, assistant professor of oncology, and several Johns Hopkins medical students, have found, as have other researchers, that taking antibiotics decreases responses to immunotherapy across several cancers, including melanoma and nonsmall cell lung cancer.

Losing Ground

While researchers continue to explore the implications for gut microbes and long-term health, that other problem — antibiotic resistance — continues to pick up steam, according to Tamma.

“We’re having fewer and fewer antibiotics that remain effective against bacteria that tend to infect patients with underlying medical problems, and we’re also losing ground against some infections that affect people who are otherwise healthy,” she says.

Increasingly, urinary tract infections (UTIs), a common and once easy-to-treat condition, are caused by microbes possessing enzymes known as extended-spectrum beta-lactamases, which neutralize a wide swath of antibiotics, including penicillins, cephalosporins and aztreonam. Patients with these resistant infections must be hospitalized to receive antibiotics of last resort through an IV, according to Tamma. Clinical trials elsewhere are investigating the potential role of new antibiotics against resistant UTIs. 

“About 50% of nursing home residents have asymptomatic bacteria. As you get older, your urinary tract can get colonized with bacteria, but it often does not cause symptoms and doesn’t need to be treated.” 

Morgan Katz

Meanwhile, Tamma is running a clinical trial testing a different approach: treating infections with phage, viruses that infect bacteria. She notes that this approach faces some challenges, including — no surprise — the bacteria’s ability to rapidly develop resistance to their viral attackers.

“If phages become an FDA-approved treatment, my guess is they're probably going to be given with antibiotics, rather than as a replacement,” she says.

Beyond the inevitable emergence of resistance and concerns about long-term consequences to health, her research, conducted with Cosgrove and their colleagues, suggests yet another reason to use antibiotics with caution: side effects. 

In a study published in JAMA Internal Medicine, their team examined medical records of 1,488 patients who had received antibiotics. Approximately 20% experienced at least one antibiotic-associated side effect, including rashes, kidney damage and subsequent infections with C. difficile.

“As an internal check, I ask myself, ‘If this patient develops a severe side effect, could I at least justify to myself that it was necessary for us to give them this drug?’” she says. 

Finding ‘That Magic Spot’

Prescribing antibiotics judiciously, however, requires good information, something that’s not always available. Based on their symptoms alone, viral infections can resemble bacterial infections but do not respond to antibiotics. When clinicians can’t distinguish between the two and face a miserable patient plus the imperative to quickly address bacterial infections, they may opt for the better-safe-than-sorry approach: an antibiotic.

New methods to more rapidly diagnose infections, such as point-of-care tests, can eliminate the guesswork.

The Johns Hopkins Hospital Adult Emergency Department recently participated in a clinical trial evaluating a point-of-care test platform that detects the three most common sexually transmitted infections: bacterial chlamydia and gonorrhea, and parasitic trichomoniasis. While conventional testing requires a day or two, this test, which was performed within the ED, could determine which condition, if any, a patient had within 30 minutes and so allow providers to make an informed decision on treatment. The results of the trial have not yet been published. 

Sara CosgroveSara Cosgrove

Quicker diagnosis isn’t the only way to cut down and refine use. Research is increasingly indicating that shorter courses can work just as well as longer ones. For example, Cosgrove, Tamma and colleagues have showed that, under the right conditions, the antibiotic regimen for bloodstream infections could be safely cut from 14 to seven days.

“You’re really trying to find that magic spot where you’ve killed the bacteria that’s causing a problem without just decimating your normal flora,” says Cosgrove, whose findings appeared in a 2021 study in Infection Control and Hospital Epidemiology.

Shortening courses is among the strategies woven into the antibiotic stewardship programs at Johns Hopkins and other institutions. These efforts to measure and improve the use of antibiotics are now required for hospital accreditation and participation in Medicaid and Medicare. But their success depends on clinicians on the front lines, according to Cosgrove. 

‘Selling Stewardship’

UTIs are a common source of unnecessary antibiotic prescriptions, including in nursing homes. If a resident develops cloudy urine and their culture comes back indicating bacterial growth, a clinician may take what they assume to be the logical course of action: prescribing an antibiotic. However, these signs do not necessarily mean the resident has a UTI and needs medication, according to Morgan Katz, assistant professor of medicine and an infectious disease physician.

“About 50% of nursing home residents have asymptomatic bacteria,” she explains. “As you get older, your urinary tract can get colonized with bacteria, but it often does not cause symptoms and doesn’t need to be treated.”

With funding from the U.S. Agency for Healthcare Research and Quality, Katz, Cosgrove and Tamma developed education programs to guide antibiotic use in skilled nursing homes and other long-term care facilities, as well as in hospitals and outpatient practices.

In all three settings, the team emphasized behavior change, collaboration and good communication strategies around prescribing, according to Cosgrove. Some of the strategies they employed, however, varied depending on the type of institution.

Stewardship in outpatient practices, in which prescribing takes place during one-on-one interactions between clinicians and patients, is a “tougher nut to crack,” Cosgrove says. In response, the team drafted language clinicians could use to explain to patients why they no longer prescribed antibiotics in certain situations. The team also experimented with designating a “stewardship champion” within a practice. This person, Cosgrove explains, acts something like pharmaceutical rep, checking in and offering support for other clinicians, “but instead of selling a new drug, they are selling stewardship,” she says.

In all three settings, their programs showed the potential to reduce antibiotic use. Among the hospitals, they saw also saw a nearly 20% drop in C. difficile infections.

At Johns Hopkins, the adult stewardship team — with two infectious disease physicians, including Cosgrove, three pharmacists, and a data expert — is unusually well staffed. The team also takes a more aggressive stance toward restricting the use of antibiotics than many other hospitals’ programs, requiring prior approval to prescribe many antibiotics, including those with broad spectrums that carpet bomb gut microbial communities and newer antibiotics, the resistance to which is so far limited. Meanwhile, stewardship team members and unit-based clinical pharmacists review cases involving antibiotics to ensure the medications are still needed or determine if they should be changed, according to Cosgrove. 

Regardless of where they practice, clinicians now are more aware of the need to use these medications wisely than those in the preceding generation, according to Cosgrove. However, she still sees a need for improvement.

“Resistance is going to continue to be a problem. Even with ‘perfect’ use of antibiotics, bacteria will still mutate,” she says. “Our goal needs to be to limit this as much as we can by not indiscriminately prescribing antibiotics.”


Valeria Fabre, Johns Hopkins associate professor of medicine, works with infectious disease physicians and microbiologists in Latin American countries to develop stewardship programs at their hospitals, and she hopes to expand the effort to outpatient facilities.

“Most hospitals [in Latin America] perform antibiotic stewardship activities, but they don’t necessarily have a program,” she says.