To Use or Not to Use: the Clinical Dilemma of Antimicrobials

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Liz Willetts

Liz Willetts, PA-C, MEM, practices medicine at a Hispanic community health center operated by Brigham & Women’s Hospital in Boston. She also works with an international team of writers for the International Institute for Sustainable Development, traveling and reporting on United Nations’ and other global environment and development policy negotiations. Liz has worked with many marginalized populations, including inner city youth, urban homeless, migrant workers, and refugees in the US, as well as rural populations in Peru, Chile and Guatemala. She graduated the University of Pennsylvania in 2002.

 

 

Understandably frustrated after 4 weeks of mild coughing, a nicely dressed businesswoman had come for an evaluation. I looked for infection in her throat, ears, and sinuses, and listened to her anterior and posterior lungs, which were clear. No sign of infection. She was in her 40’s, slim, and looked well, and had no fever. I didn’t give her an antibiotic. And she was furious.

I asked her why she thought she needed an antibiotic.

“Because all my coworkers got antibiotics for their coughs, and I want some too!,” she replied.

I held my ground. She stormed out of the room. I was, she said, “a waste of time.”

As much as I am a prescriber I am also a gatekeeper for community health.

Public health reports show that as much as 50% of the time in the U.S. antibiotics are prescribed when they are not needed. In 2010, we prescribed 258 million courses of antibiotics, meaning we used antibiotics 129 million times more than necessary that year.

We are trying to cut down.

 

U.S. Center for Disease Control finds that those in southern states write and receive significantly more antibiotic prescriptions than those in the west. New England Journal of Medicine 2013 368:1461-1462 April 11, 2013

Antibiotics (antibacterials), and all other antimicrobials, are powerful substances. They kill organisms.

Microbes – bacteria, viruses, fungi, protozoa and parasites – get a bad rap. But that is because we forget that our bodies are ecosystems of microbes. We actually have about the same number of cells as we do microbes, approximately ~37 trillion of each and we need those microbes as much as we need our cells to survive and function.

Every time we use an antimicrobial drug we shock our body’s complex system of microbes. The drug is specific enough to kill a sub-population of structurally similar microbes, but not selective enough to isolate a single infection-causing microbe. So we kill more microbes than are necessary every time we use these drugs.

Ever have diarrhea or a yeast infection after taking an antibiotic? These are side effects of a disrupted intestinal and vaginal microbial ecosystem, respectively. Digestion of food is a process that relies on our innate intestinal bacteria. Vaginal health requires low acidity, and antibiotics, which increase acidity, foster growth of yeast, a microbe that flourishes in acidic environments.

The fine line of when to or not to prescribe an antimicrobial shifts as clinical judgment is refined. Ideally we prescribe when we think the immune system – which regulates the balance of our microbial ecosystems – can no longer fight on its own against overly harmful microbes. This is puzzlingly vague, and perhaps cultural. In the U.S., a country notorious for work-oriented people, our barometer for when to prescribe an outpatient antibiotic in cases of borderline illness may unofficially be associated to whether or not you have stayed home from work due to your illness.

The medical provider’s job is to keep the overall immune system tuned up and strong, and sometimes that is best done by not using an antimicrobial.

In outpatient medicine, antibiotics are supposed to be a last resort medicine to treat some infections. But we’ve been prescribing them to treat the annoyance of being sick, even when our immune systems are actually strong enough to recover.

The cough of my patient above did not necessarily mean she was infected, or infectious. It is more likely that after her viral cold cleared her body was reacting to a post-viral inflammatory state, something some people are more sensitive to than others.

Overuse of antimicrobial drugs is a problem for public health. Frequent use causes resistance, a phenomenon where microbes evolve and are no longer responsive to the drugs. A 2015 Health Affairs policy brief estimated that by 2050 there will be 10 million antimicrobial resistance–related deaths worldwide.

But antimicrobials are in high demand. They are so powerful that other industries use them for reasons other than to treat infection.

This is the case in global health nutrition where since 1999 guidelines have recommended routine oral antibiotic treatment for the 20 million children under 5 years who have severe acute malnutrition despite not having symptoms or signs of infection (as of 2013 this is five days of amoxicillin plus therapeutic food). It is hoped that antibiotics will have a positive impact on weight gain, immune systems, and overall survival, however large well-respected studies published in the New England Journal of Medicine in 2013 (Malawai) and in 2016 (Niger, funded in part by Médecins Sans Frontiers) provide contradicting evidence of its efficacy.

In an oddly similar manner, the food industry has given sub-therapeutic doses of antibiotics to our U.S. food animals since the 1950s to enhance animal growth and improve survival. The U.S. National Academy of Sciences reported nearly two decades ago that the U.S. used more than 6 times the amount of antibiotics on food animals than it did on humans and today about 70% of our US annual antibiotic supply is given to livestock, poultry and aquaculture. In attempts to be more efficient, geneticists are even engineering plants to produce seeds that contain antibiotics, thus growing enhanced animal feed.

Antibiotics are routinely given to livestock, poultry, and aquaculture in the U.S. to enhance their growth and survival.

Antibiotics are leaking into our environments and affecting other organisms. They pass from human or food animal waste and are uptaken by plants and consumed by other organisms in the ecosystem, and leak into the ground water. We are making it increasingly likely that resistant bacteria develop in food animals and spread throughout our ecosystems and soils. Indeed, this is already happening.

The World Health Organization (WHO) calls our global culture of antimicrobial use “irrational.”

For the last 20 years, they have been asking us – prescribers, governments, and the food industry – to be more rational. As described in the Health Affairs brief, U.S. policy attempts to regulate the use of antibiotics in animal feed have been hamstrung by battles between medical and scientific experts and the pharmaceutical and meat industries. On the ground, bridging organizations like the US Public Interest Research Group (PIRG) are focusing on converting fast food meat-supplying giants like McDonald’s, Tyson Foods, and Subway etc. to stop serving meat raised on antibiotics, particularly those used in human medicine. Lessons can certainly be learned from Europe who banned use of any human-relevant antibiotics in food animals as well as use of antibiotics as growth promoters altogether, back in 2006, though implementation of the policy continues to be difficult. Several other countries have attempted similar efforts.

The development of national drug strategies, including establishing national formularies called Essential Medicines Lists (EMLs), is an example of how the WHO hopes to guide antimicrobial use world-wide. EMLs take local disease prevalence and antibiotic susceptibility into account, with an aim to enhance population-level care and accessibility to appropriate medicines. These are factors that increase drug efficacy and reduce costs. The listing is also intended to serve as a health basis for focus and expenditure in the pharmaceutical sector, and in the U.S. to guide insurance coverage for antimicrobials. As of 2017, 156 nations have national medicines policies but the concept still faces resistance in some middle income and industrialized countries despite high-level endorsement of its effectiveness. Here is a 2011 study published in the American Journal of Public Health touting the benefits to U.S. healthcare for the application of Essential Medicines to Medicaid preferred drug lists.

WHO poster celebrating the benefits of Essential Medicines.

Clearly, cross-sectoral monitoring is needed to input ‘rational’ use of antimicrobials in the future. But there are no internationally agreed standards for collection of data and reporting at national levels on use or resistance in human health, and no harmonizing standards across medical, veterinary and agricultural sectors. (I encourage anyone prescribing antimicrobials to read the eye-opening WHO 2015 Global Action plan on Antimicrobial Resistance.) The U.S.-based Union of Concerned Scientists advocates for U.S. monitoring on antimicrobial data, which may become easier now that hospitals are required to establish antimicrobial stewardship programs.

But let’s get back to the clinic, and look at what resistance means to adult and pediatric patients.

A common condition likely to be affected soon is vaginal yeast infections – which are itchy, annoying, and seen every day in clinic. Fluconazole, the antifungal pill we prescribe when the over the counter antifungal cream isn’t working, is listed under “serious threat” to resistance from the Candida sp. fungus according to the U.S. Center for Disease Control’s (CDC) report Antibiotic Resistance in the U.S., 2013. Other microbes on this list showing “serious threat” of resistance to multiple drugs, and are common in outpatient illness, include Pseudomonas aeruginosa (many diabetic foot infections), Salmonella, Shigella, and Campylobacter (bacterial diarrhea), Streptococcus pneumoniae (many ear, sinus, and lung infections/pneumonia), and Tuberculosis.

Some bacteria have particularly impressive abilities to evolve, and therefore resist, antimicrobial drugs. Neisseria gonorrhea, the sexually transmitted bacterial infection whose inflammatory reaction can cause infertility in women is on the CDC “urgent threat” of resistance list. Over the last decades gonorrhea has steadily overcome most major classes of readily available antibiotics including sulfas, penicillins, tetracyclines, and fluoroquinolones, and there are cases of resistance already reported against the currently used drug, ceftriaxone, which is an injectable of the cephalosporin class. The need for robust reproductive health education for teenagers and, particularly, male patients, is vital to reducing the prevalence of this infection.

There is no plan for when full resistance to our existing antimicrobials finally occurs. Our U.S. medical schools do not teach us how to medically manage infections without these drugs.

Hygiene and health education are the tools that could reduce the prevalence of infections requiring antimicrobials. But, globally, communities that most need these tools struggle against policies, or cultural norms, that prevent robust sexual education and/or access to preventative health care.

Let me turn the corner for a moment, and expose another complex angle of the antimicrobial issue.

When we broadly ignore problems related to access to medical care interesting things happen. One that many of us might not realize is the black market for antibiotics. From my Latino patients I’ve learned that the street price for a tablet of amoxicillin is a little over $1.00 in the U.S., and that tablets are bought and used in random quantities.

In the U.S., our national culture guides us to buy medicines with a prescription. But for many Latinos, self-medication is part of the family cultural heritage. Antibiotics, like many medicines, are available without prescription in many Latino countries, and are used freely. In the U.S., this aspect of Latino culture continues because many Latinos do not have appropriate access to medical care. This translates to not having access to affordable, appropriate prescriptions, nor to the cultural guidance and health literacy that comes with it. There are ~30 million Latino residents in the U.S, and 11.2 million undocumented immigrants, most of whom are Latino. The traffic and sale of black market antibiotics is surely fairly fluid amongst a sub-population of this large Latino community and across borders.

Even in just these few examples, it’s easy to estimate that we are using hundreds of millions of courses of antimicrobials in excess, inappropriately, and for reasons other than to fight infection, worldwide. To chart a new course on these professional, industrial and cultural trends is daunting.

Problem solving agendas were taken up in October 2016 at a joint Symposium on Antimicrobials hosted by the World Intellectual Property Organization, the World Trade Organization and the WHO. Underlying the urgency of this symposium was the realization that antibiotic consumption in humans increased 36% between 2000 and 2010, while new antibiotic research and design has, paradoxically, nose-dived due to weak return on investment. With good reason, the focus of this event was discussion of alternatives to antimicrobials in health care, like vaccines, probiotics, prebiotics, immune products and enzymes and gene products.

To me this event serves as a clinical wake up call to start re-learning, if not newly learn, how to manage infections without antimicrobials, and start to lessen my reliance on these drugs.

At my hospital system I’ve observed that adult specialists, including gynecologists and gastroenterologists, who see patients with recurrent vaginal or intestinal issues, frequently incorporate trials of probiotics into the treatment plans of patients as a means to regulate or reset microbial balance in favor of beneficial rather than pathogenic bacteria. Probiotics are straight forward – live microbes (lactobacillus, bifidobacterium, streptococcus, bacillus) that can be taken in a tablet form. These organisms can also be found in common foods like yogurt, kefir, specific cheeses, sour dough bread, dill pickles, sauerkraut, kimchi, tea, beer, and wine. However, official U.S. governmental sources bound by scientific research protocols continue to report that strong evidence is lacking.

Prebiotics are found in human breast milk.

An interesting 2010 Clinical Report by the American Academy of Pediatrics discusses the benefits of prebiotics – food containing nondigestible fiber or ingredients (inulin, oligofructose, galactooligosaccharide) that can improve the growth of probiotics. Prebiotics are found in bananas, artichokes, asparagus, garlic, onion, leeks, jicama, root vegetables, psyllium, honey and human breast milk.

If we are going to continue to be medically relevant to our patients outpatient providers will need to make a strong effort to rely on alternatives to antimicrobials.

To future ill patients, if there was one thing I could say it would be:

Don’t ask your prescriber for antibiotics. Ask them if your immune system really needs it.