Dr. Catherine Liu’s job is a balancing act.
An infectious disease clinician-researcher at Fred Hutchinson Cancer Research Center, Liu knows that antibiotics and other microbe-fighting drugs are lifesavers for cancer patients who are especially vulnerable to infections.
But prescribing antimicrobials too often or too broadly can lead to drug-resistant pathogens that are hard — if not impossible — to treat. Antibiotics also disrupt the gut microbiome, which scientists are learning plays a key role in immune responses.
As the recently hired director of antimicrobial stewardship at Fred Hutch’s clinical care partner, Seattle Cancer Care Alliance, Liu looks for ways to balance the drugs’ lifesaving good against the threat of resistance, particularly in light of an alarming paucity of new antibiotics in the drug development pipeline. That mission is all the more urgent because the risk posed by antimicrobial resistance extends beyond any individual patient.
Antimicrobials promote resistance by killing susceptible bugs, leaving any that are naturally drug-resistant, or that develop resistance through mutation, to divide and grow in the body. Drug-resistant bacteria, viruses and fungi can then spread to new hosts and in some cases even spread their resistance genes to different microorganisms, posing a risk to society at large.
For this reason, Liu said, antibiotics and other antimicrobials are unique among medications, a “shared resource” that we need to preserve, much as we steward our environment and natural resources.
“If you’re taking Lipitor for your cholesterol, that has no impact on anyone else,” she said. “But if you’re taking an antibiotic, it has an effect on you and also on other people down the line and their ability to use that antibiotic.”
Everyone knows that penicillin, discovered in 1928 and first used widely in the 1940s, revolutionized modern medicine. But to understand the impact that penicillin and newer antibiotics — as well as anti-fungal drugs and antivirals — have had on cancer care, you have to understand the impact that cancer and its treatment have on infection risk and immune response.
Surgery, radiation and chemotherapy — for decades the three pillars of cancer therapy — increase infection risks in multiple ways. Surgical incisions, as well as central lines for delivering chemotherapy, serve as portals for germs to enter the body. Radiation and chemotherapy can break down cells lining the mouth, gastrointestinal and respiratory tracts that ordinarily serve as barriers to germs. And these treatments can weaken or even destroy the body’s immune system, already burdened by the cancer itself.
This is especially true for patients who need blood stem cell transplants. Preparing a patient for the transplant means essentially ridding the body of its cancerous immune system and allowing a new one to come in and set up shop. Until the new immune cells take hold, a person’s natural defenses against infections are rendered useless. Even microbes that would normally be harmless can wreak havoc.
The threats come from both outside and inside the body.
“Our body — our skin, our gut — is covered in microbes,” Liu said. “Many of these organisms are important for functioning. But destruction of your gastrointestinal tract from chemotherapy — chemo can be especially toxic to GI [cells] — allows things that live in your gut to go outside your gut and cause an infection in your bloodstream.”
While preventing infections through rigorously enforced hand-washing campaigns, central line sterilization and other hospital measures have played a key role in patient survival, antimicrobials have “really changed the landscape of our ability to treat transplant patients,” Liu said. Many hard-won improvements in cancer survival would not have been possible without these drugs.
Antibiotic stewardship focuses on preserving those gains by protecting the power of antibiotics.
The Centers for Disease Control and Prevention estimate that at least 2 million Americans a year become infected with drug-resistant bacteria and 23,000 of them die of their infections. New antibiotics and other antimicrobials are desperately needed, but development has stalled for both scientific and economic reasons. Developing antibiotics for one class of bacteria, the so-called Gram-negative bacteria, is particularly challenging because of their hard-to-penetrate double-layered membrane and ability to actively expel drugs that do get through that wall. And preserving the effectiveness of any new antibiotics would mean using them sparingly as a last resort — meaning a much lower return on investment for pharmaceutical companies compared with developing high-priced cancer drugs or drugs used to treat chronic conditions such as high cholesterol or diabetes.
At a May 2016 press conference, CDC Director Dr. Thomas Frieden warned against what he called “nightmare bacteria” that are resistant to carbapenems, the broadest of the broad-spectrum antibiotics that work against almost any bacteria. Only one antibiotic — colistin — still works against carbapenem-resistant superbugs. It was developed in the 1960s and 1970s and went largely unused because it is so toxic to patients.
“We risk being in a post-antibiotic world,” Frieden said at the time. “That wouldn’t just be for infections that you think of as bad infections — pneumonia, urinary tract infections, that’s bad enough. That could be the 600,000 Americans a year who need cancer treatment for whom we just assume we’ll be able to treat infections. We may lose that ability.”
Liu has a stark memory of treating a patient with a highly resistant infection. The patient had contracted a multi-drug resistant form of a Gram-negative bacterium called pseudomonas while working in West Africa. The patient survived, she said, but only after a long stay in the hospital.
“Pseudomonas is a very clever bacterium. It has lots of ways of developing resistance,” said Liu. “It can be very serious and life-threatening, and we are running out of agents to treat the multi-drug resistant forms.”
Multi-drug resistant bacteria emerge among patients who are frequently exposed to long courses of broad-spectrum antibiotics, Liu said. They can also emerge in resource-limited settings where antibiotics are sold over the counter with no clinical oversight on who takes which drug for how long.
In January, the CDC reported the death of an elderly woman in Nevada who had become infected with a multi-drug resistant superbug during an extensive stay in India, where she had been treated for a broken leg. She died of a Klebsiella pneumoniae infection — another Gram-negative bacterium — that was resistant to every antibiotic available in the U.S.
In response to the threat posed by antibiotic resistance, the Infectious Disease Society of America and other organizations, in addition to calling for stewardship programs, have taken the lead in calling for pharmaceutical companies to develop new antimicrobials.
While heading off the development of resistance is the major aim of antibiotic stewardship, it is not the only goal. Another is to head off the collateral damage that antibiotics can cause.
Take Clostridium difficile, or C. diff, a spore-forming, toxin-producing bacterium that can take over the large intestine and cause severe, life-threatening diarrhea. In most people, the gut microbiome is diverse enough that C. diff can’t muscle in and take over. But antibiotics can wipe out enough normal “good” bacteria to upset a healthy balance, allowing C. diff to spread and do its damage.
Emerging studies are also beginning to look at possible associations between antibiotic use over time and the risk of colorectal cancers. Other studies have raised questions about whether antibiotics could interfere with the impact of the newest pillar of cancer treatment, immunotherapies, which harness the power of a patient’s own immune system.
And finally, there’s the impact of multi-drug resistant infections on wallets. Resistant infections are more difficult to treat, often requiring longer hospital stays and more time away from work. Preventing resistance, then, saves dollars, which is no small concern in the face of the soaring cost of cancer care.
In raising the specter of resistance, Liu and other infectious disease researchers don’t intend to scare patients — or their physicians — away from antibiotics. They do not want patients to be undertreated. But they do want all of us to use the miracle drugs that we have appropriately — and stop taking them for granted.
“Antimicrobial stewardship is a coordinated effort to ensure rational use of antibiotics, antifungals, antivirals, all antimicrobial agents at an individual patient level, making sure that you are choosing the right drug at the right dose using the right delivery method for the right duration,” Liu said. “A lot of the work will entail reviewing and developing guidelines and standardized approaches for management of patients with specific infections while recognizing that each patient is an individual.”
Liu’s role at SCCA is not to overrule an attending physician’s prescription but to offer recommendations and guidelines. Part of this effort will mean tracking and monitoring antibiotic use in the SCCA patient population and asking whether patients are taking the appropriate drug. If a patient is on a broader-spectrum antibiotic than is actually needed, for example, Liu’s team can provide guidance.
“Broad-spectrum antibiotics can treat lots of different kinds of bacteria,” she said. “Sometimes we use those broad spectrum types when a patient is very sick and we don’t know what’s going on. But once you identify the specific bug that’s causing that infection, you want to give targeted therapy. This allows you to minimize potential side effects and limits the risk that resistance will develop. The more broad the spectrum, the more pressure you put on all bacteria to resist that antibiotic. Our goal is to use the narrowest spectrum possible.”
Improved rapid diagnostic testing to identify the specific bacteria is part of the strategy; diagnostic uncertainty drives the use of broad-spectrum antibiotics by physicians who would rather be safe than sorry. But it’s possible to “de-escalate” to a narrower, more targeted antibiotic once the microbe is identified.
Ultimately, Liu and her team hope to encourage a “stewardship mindset” in physicians and patients alike.
“We need to begin to appreciate that antibiotics are a precious resource,” she said. “When we prescribe, we need to think about the consequences not just for the individual patient but for the rest of society and for public health. We all need to be stewards.”
Mary Engel is a former staff writer at Fred Hutchinson Cancer Research Center. Previously, she covered medicine and health policy for the Los Angeles Times, where she was part of a team that won a Pulitzer Prize for Public Service. She was also a fellow at the Knight Science Journalism Program at MIT. Follow her on Twitter @Engel140.