The escalating problem of antimicrobial resistance in the U.S. is becoming more dire each year.
2016's watershed moment may have been the country's first report of mcr-1, the gene that confers resistance to colistin, found in a sample of Escherichia coli cultured from a patient with a urinary tract infection (UTI). Fortunately, the infection was susceptible to other antibiotics.
In 2017, however, January's big resistance news was all the more harrowing because it involved a patient's death. A Nevada woman in her 70s died last September of a wound infection that was resistant to all 26 antibiotics available in the U.S. The culprit pathogen was found to be Klebsiella pneumoniae, part of the infamous "superbug" group of carbapenem- resistant Enterobacteriaceae (CRE), which have also been implicated in prior pan-resistant gram-negative bacterial infections.
Although general internists would not be on the frontlines of critical care for such a patient, they are poised to assume a key role in tackling the increasingly formidable threat of antimicrobial resistance, experts said.
"Primary care internists are supposed to be the tip of the spear. Even though you may not solve the entire problem, you set the chain of events in motion so that the problem can be solved," said ACP Member Ashwin Vasan, MD, PhD, MSc, an assistant professor of population health and medicine at the Columbia University Mailman School of Public Health and College of Physicians and Surgeons in New York.
The role of prescribing
Internists play a crucial role in the appropriate initial diagnosis and treatment of infections, especially when prescribing antibiotics, said Aaron Glatt, MD, FACP, chairman of the department of medicine at South Nassau Communities Hospital in Oceanside, N.Y. "There's a tremendous amount of inappropriate antibiotic usage in the outpatient setting," he said.
From 2010 to 2011, at least 30% of antibiotics prescribed in outpatient settings in the U.S. were likely not needed at all, CDC researchers estimated in a JAMA study published in 2016. Moreover, total inappropriate outpatient antibiotic use may be closer to 50% when including both unnecessary use and inappropriate selection, according to the CDC.
In 2015, the Obama administration unveiled the White House National Action Plan for Combating Antibiotic-Resistant Bacteria, with the aim of decreasing unnecessary antibiotic prescribing by 50% by 2020. (However, it is unclear how the current administration will approach this issue.)
In order to meet this goal, total outpatient antibiotic prescribing in the U.S. would need to fall by 15%, with most of the reduction coming from limiting unnecessary use of antibiotics for acute respiratory conditions, which account for 44% of outpatient antibiotic prescriptions, according to an October 2016 joint statement released by the CDC and about a dozen national health organizations, including ACP and the Infectious Diseases Society of America (IDSA).
"It's clearly shown that, not internists specifically, but primary care physicians do a particularly poor job of treating certain nonantibiotic-treated infections with antibiotics," said Dr. Glatt, also a spokesman for the IDSA and district president-at-large for the Long Island Region of ACP's New York Chapter.
Although the problem of inappropriate use is not restricted to one particular class of antibiotics, fluoroquinolones (e.g., levofloxacin, ciprofloxacin, moxifloxacin) have caused growing concern, he noted. In 2016, the FDA announced that it would strengthen the "black-box" warning on these common medications because the serious side effects generally outweigh the benefits for patients with sinusitis, bronchitis, and uncomplicated UTIs.
There are several reasons why physicians prescribe antibiotics inappropriately, such as pressure from some patients, whose ideas of a pill-derived quick fix for viral infections are "incorrect and dangerous," Dr. Glatt said. In a recent public health poll of 600 New York City and Long Island residents, his hospital found that about 12% of respondents admitted to pressuring their physicians for an antibiotic, even after they were told they didn't need one.
Such pressure can lead some physicians to inappropriately prescribe antibiotics to keep their patients happy instead of providing education, said Jose A. Vazquez, MD, FACP, a professor of medicine and chief of the division of infectious diseases at the Medical College of Georgia at Augusta University.
It's often difficult and time-consuming to educate patients and reassure them that their virus will go away with time, liquids, and rest, he said. "They're looking at you like, 'But all the doctors I've ever seen have given me antibiotics for this, and if I don't get this, I know I'm going to get worse—and if you don't give it to me, I'm not coming back to you; I'm going somewhere else,'" said Dr. Vazquez.
If a patient is resistant to the idea of forgoing an antibiotic, Dr. Glatt suggested spending the time to explain why these drugs would actually be harmful (e.g., drug toxicity, drug resistance, cost). "All of these things are tremendously important reasons for patients to say, 'Thank you, Doctor, for not prescribing me an inappropriate drug,'" he said.
Antimicrobial resistance shows no signs of relenting, so it's critical for physicians to move beyond simply reading journal articles and tailor their prescribing practices to their local communities, said Dr. Glatt. "Typical agents that you thought would be effective in the past are no longer effective, so one has to be very much aware of the local resistance patterns in your area where you practice," he said.
However, a lot of physicians are neglecting to do this, said Dr. Vazquez. "As a matter of fact, when I give lectures, most physicians are not even aware of their susceptibility patterns in their area," he said. One way to learn about these patterns is through antibiograms, which provide local data based on isolates tested in hospitals' clinical microbiology laboratories.
Most hospitals publish antibiograms so that local physicians can become familiar with resistance and susceptibility patterns in their communities, said Dr. Glatt. "The community will be somewhat reflective, but not necessarily totally reflective of, the local hospitals," he said.
The CDC also has maps on its website that denote resistance and susceptibility patterns, which vary widely in different regions across the country, Dr. Vazquez noted. "For instance, in areas like Montana, Idaho, the Dakotas, they actually have a lot lower resistance rates than in the Mid-Atlantic (New York, Pennsylvania, and New Jersey), which has some of the highest rates of resistance," he said.
In addition to knowing what's treatable and what's not treatable within the context of their clinical service and paying attention to the local epidemiology, demography, and risk profiles of the communities they serve, internists should work to collaborate, said Dr. Vasan.
"They should have really clear and robust links with feedback loops to specialist providers, who can do more in-depth investigations and/or prescribe more specialized treatments," he said. "They also need to have good links with the public health system for reporting and surveillance."
In addition to following CDC guidance on public health issues, internists should be familiar with the reportable conditions and know who (and when) to call at their local and state departments of health, Dr. Vasan said. "It's really not that time-intensive. … Usually these are resources available online," he said.
In between educating patients and being good antimicrobial stewards, internists also need to be aware of new resistances as they emerge, experts said.
Underscoring the urgency of uber-resistant bugs, the World Health Organization (WHO) in February released a list of "priority pathogens" for the research and development of new antibiotics (see sidebar). In 2013, the CDC published a similar report, which outlined the top 18 drug-resistant threats in the U.S., the most urgent threats being Clostridium difficile, CRE, and Neisseria gonorrhoeae.
Of all the types of antibiotic resistance, the biggest concern for the internist is the resistance seen in the community. E. coli and other gram-negative bacteria dominate both organizations' lists of pressing threats and are the main offenders in terms of antimicrobial resistance, said Helen W. Boucher, MD, a professor of medicine in the division of geographic medicine and infectious diseases at Tufts Medical Center in Boston.
"These are bacteria that cause everything from UTIs to life-threatening pneumonias in the ICU," she said. "These bugs have become resistant to many, many of our antibiotics, including last-ditch and known-to-be-toxic drugs."
One place these resistant gram-negatives impact internists is when they strike young, otherwise healthy people in the form of UTIs that aren't easily treated, said Dr. Boucher. "That's happening more and more often, so these young and otherwise healthy people have to have IVs placed and receive antibiotics intravenously for two weeks, and that is a big problem," she said.
Physicians have used fluoroquinolones to treat UTIs for 30 years, but increasing resistance of E. coli to ciprofloxacin is a big concern, said Dr. Vazquez. "So when the internist gives cipro and they don't know about the resistance, patients come in to the emergency room in septic shock with a pyelonephritis instead of a UTI," he said. Worldwide, the pooled ciprofloxacin resistance in community-acquired E. coli UTIs was estimated to be 27% in a 2015 systematic review and meta-analysis published in BMC Infectious Diseases.
Dr. Boucher said internists might see a clinical failure when using first-line therapies in patients who walk into the office with seemingly simple UTIs. If patients are no better after three days (and certainly if they become even sicker with fever), "It's important to send a culture to make sure you're not dealing with resistance," she said.
Dr. Vazquez noted that methicillin-resistant Staphylococcus aureus (MRSA) remains a major concern. The estimated proportion of community-associated MRSA out of all S. aureus infections in the U.S. is as high as 65%, according to a meta-analysis published in 2013 by PLoS One. "Internists are the first line of defense. They see patients before we as specialists do … so they need to know how to recognize it and think about it as a possibility so that patients get the care that they need quickly in the right circumstances," said Dr. Boucher.
Gonorrhea, a "crafty" gram-negative infection, continues to be a top concern for antimicrobial resistance, said Kimberly A. Workowski, MD, FACP, a professor of medicine at Emory University School of Medicine in Atlanta and lead author of the CDC's 2015 guidelines for treating sexually transmitted diseases (STDs).
As the number of cases increases worldwide, a growing proportion are likely drug-resistant, she said. "Gonorrhea has a really unique ability to develop antimicrobial resistance. … Despite multiple antimicrobials that have been developed, this organism has figured out a way to develop resistance," Dr. Workowski said.
Trends point to a growing resistance of N. gonorrhoeae to the only available treatment regimen, the CDC reported in 2016. The current treatment recommendation is dual therapy with oral azithromycin and ceftriaxone injection, but options are very limited for patients who cannot tolerate cephalosporins, said Jeanne Marrazzo, MD, MPH, FACP, a professor of infectious diseases and director of the division of infectious diseases at the University of Alabama at Birmingham School of Medicine.
"We're really in a very uncomfortable place right now, given the lack of options we have for gonorrhea treatment," she said, noting that not so long ago, there were five different therapies for the infection. "It's a public health emergency, really. There are some [new] drugs on the horizon, but none of them have really become available or mainstream."
Only three new products in development are currently in clinical trials for gonorrhea treatment, so "There's a meager pipeline," agreed Dr. Workowski.
Although not on lists of urgent threats, Mycoplasma genitalium, a sexually transmitted infection first identified in the 1980s, appeared as an "emerging issue" in the CDC's 2015 STD treatment guidelines. "It's an infection that is probably most concerning for its emerging role in persistent urethritis, mostly in heterosexual men," said Dr. Marrazzo.
Although many physicians don't know much about M. genitalium, it causes about 20% of all urethritis and is the second most common cause of nongonococcal urethritis after chlamydia, said Dr. Workowski.
There is a subset of men with urethral inflammation syndrome that is not due to chlamydia or gonorrhea, Dr. Marrazzo said. "It looks like M. genitalium is responsible for a not-insignificant proportion of those cases, where not only did we not find another etiology, but it tends to be more difficult to treat with standard antibiotics for urethritis," she said. "It is something to think about if you see a man who has persistent urethritis."
The bug's role in female reproductive tract infections is still under investigation, Dr. Marrazzo added. "But there are pretty good data to say that it may cause cervicitis, like chlamydia and gonorrhea, and then can cause upper tract infections like pelvic inflammatory disease," she said. "How common that is, we really don't know, but data are accruing to say that it does occur."
As researchers continue to learn more about this organism, the difficulty in the U.S. is that there is no FDA-cleared, commercially available test to detect it.
Specific testing with nucleic acid amplification tests is available in some medical centers, but in the absence of validated tests, M. genitalium infection should be suspected in men with persistent urethritis, Dr. Workowski said. However, in countries that do have commercially available assays, it has become evident that M. genitalium has quickly developed a resistance to the antibiotics commonly used to treat urethritis in men, she said.
"Over the last five years, there's been a dramatic decrease in azithromycin's effectiveness against this organism," said Dr. Workowski. "Doxycycline doesn't work well for this organism, and azithromycin has had decreased effectiveness." CDC guidelines recommend empirical treatment with moxifloxacin in men with persistent urethritis, although resistance is developing to this regimen, as well, she added.
Finally, the threat of multidrug-resistant and extremely drug-resistant tuberculosis (TB) is not to be ignored, experts said. About a third of the world's population is infected with TB, one of the deadliest infectious diseases, said Dr. Vazquez.
Although the U.S. does not have the high TB infection rates of some other countries, immigration makes a difference. Last year, about 68% of TB cases in the U.S. occurred among foreign-born persons, the CDC reported in March. Clinicians should screen for latent TB infection in populations that are at increased risk for TB, according to 2016 U.S. Preventive Services Task Force recommendations.
"Depending on the risk factors, if your patient is from outside this country, you have to think of TB," said Dr. Vazquez, noting that symptoms overlap with community-acquired pneumonia (e.g., fever, dyspnea, cough, infiltrate on chest X-ray). "Most internists refer to an infectious disease or pulmonary [subspecialist for treatment], but they're the ones that make the diagnosis. … It's definitely a key learning point for primary care doctors."
If TB is susceptible to drugs, it usually takes an average of six months of treatment with four medications to eradicate the infection, Dr. Vazquez said. Resistance can mean much longer treatments in the range of 12 to 24 months, he said. "The extremely drug-resistant TB is serious because those patients, if they're not put on the right drug and you're not thinking about extreme drug resistance, then they will be on the wrong drug for a period of time," said Dr. Vazquez. "That creates an increase in morbidity and mortality in that individual, but it also increases the spread of TB in that individual that's supposed to be treated."
The WHO received pushback from the public health community for leaving TB off its priority list. However, Dr. Boucher noted that WHO leaders have made it clear that they recognize drug-resistant TB as a major problem, and there are already global efforts underway to combat it.
"I think our focus on the antibiotic resistance, certainly in the U.S. with the Presidential Advisory Council and other groups, has been on the problems of standard bacteria, the gram-positives and gram-negatives," she said. "But we all agree that TB is a huge problem and is not to be overlooked."