Antibiotic resistance: A global crisis in the making

April 19, 2018
Petrii dish
A petri dish growing methicillin-resistant staphylococcus aureua (MRSA), bacteria that have become resistant to many of the antibiotics used to treat ordinary staph infections. Photo provided

A deadly type of bacteria accidentally released from a laboratory spread across an expansive property, infecting several rhesus macaques. Two died. An employee tested positive. Authorities rushed to contain the possible spread of a potentially fatal illness called Whitmore's disease that affects humans and animals. 

What sounds like the plot of a Michael Crichton novel is not fiction at all. This incident happened in 2015 at an academic research center in Louisiana. And while pandemics make for gripping reading and disaster movies, there is an even scarier reality: In 2018, you could indeed catch an infection that doctors cannot treat.  

Antibiotics, which doctors prescribe every day to cure infections, are not working against certain bacteria, rendering one of the world’s most valuable classes of medicines useless. When bacteria stop responding to antibiotics, it leaves humankind wide open for — as the World Health Organizations calls it — “a global crisis in the making.”  

There are bacteria, like the type that caused Whitmore’s disease, that have become highly resistant to several classes of antibiotics — including carbapenems, which are referred to as the “antibiotics of last resort,” by the National Institutes of Health. 

That in a nutshell is what is keeps experts like Amanda Parks, M.D., an assistant professor in the Division of Infectious Diseases, up at night. Parks was recruited to MUSC to ensure everything possible is being done to promote appropriate use of antibiotics.   

“This is the beginning of what has been theorized as the ‘post-antibiotic era,’ the time after antibiotics,” she explained. “Most physicians have never been in that position — faced with treating an infection that is resistant to all antibiotics. It only takes one time to realize that it’s terrifying.”

Drug resistance is upon us, she said, but it wasn’t unexpected. 

“We’ve known this was going to be a problem, and it’s a direct effect of wanton, injudicious over-prescription of antimicrobials, which has led to the emergence of drug-resistant bacteria.” 

Shortly after Alexander Fleming discovered penicillin in 1928, scientists discovered emerging resistance to penicillin. As predicted, bacteria have evolved and adapted to specific drugs, making the germs less susceptible or resistant. And now hospitals are challenged with managing deadly drug-resistant infections. For decades, it was projected that this could become a problem, and now it has.

Antimicrobial stewardship

More than 2 million people in the U.S. become ill every year as a result of antibiotic-resistant infections, according to the Centers for Disease Control and Prevention, and 23,000 die. Worldwide that number is 700,000 a year, a statistic that is said to be on the low side, according to the 2014 Review on Antimicrobial Resistance, an influential study that was commissioned by the United Kingdom Department of Health and referenced widely by the National Institutes of Health.

 To help combat this, Parks believes that providers should ask questions before prescribing antibiotics. 

“First — do they really need antibiotics?” she asked. “A lot of times, people are incorrectly presumed to have infections, and they receive the antibiotics unnecessarily,” she explained. “Secondly, if they do actually have an infection, is it an infection caused by a bacteria or a virus? If it is a virus, antibiotics won’t treat a virus. If it is a bacteria, what is the appropriate antibiotic to use? Lastly, what is the appropriate duration of treatment? Does everyone need two weeks of Ciprofloxacin? Probably not.”

Joel Melroy, Pharm D., director of Adult Pharmacy Services, agreed, adding that well-meaning parents may ask their pediatricians for specific antibiotics when their children are sick. And despite decades of warnings, doctors continue to overprescribe antibiotics for colds, flu, and upper respiratory infections, even though most are caused by viruses that antibacterial drugs can’t help. “Giving an antibiotic for infections that are not bacterial contributes to this growing problem,” he said. 

That “shotgun approach,” as he called it, worries Melroy.  

“One of the fears we all have is antibiotic resistance. Beginning therapy on broad-spectrum antibiotics may be appropriate as long as therapy is transitioned to the most suitable therapy to focus on specific infections as soon as specific micro-organism information is available. If we don’t de-escalate therapy to focus on specific infections, then we are not only impacting one patient, we have potentially populations of people who may be affected due to antibiotic resistance.”

Shawn MacVane, Pharm D, a clinical pharmacy specialist in infectious diseases, is focused on this crisis.  MacVane collaborates with Parks, John Gnann, M.D., director of the Antimicrobial Stewardship Program, and Terry Dixon, M.D., Ph.D., a pediatric infectious disease specialist involved in the program. This team of physicians and pharmacists is tasked with improving the appropriate use of antimicrobials by ensuring the appropriate antimicrobial drug regimen, dosage and duration are used.

MacVane said that as high as 30 to 50 percent of the antibiotic prescriptions written are prescribed inappropriately, relating figures published by the CDC. Repeated exposure, he said, can lead germs to become resistant to the drugs.

Take methicillin-resistant staphylococcus aureus (MRSA), bacteria that has become resistant to many of the antibiotics used to treat ordinary staph infections. 

MRSA, which has developed resistance to penicillins and cephalosporins usually used to treat staph infections, can be deadly. Patients with serious MRSA infections require hospitalization for treatment with alternative antibiotic regimens. 

But according to Parks, compared to a new resistant strain of CREs, or carbapenem-resistant enterobacteriaceae, MRSA is now just a superbug lite. 

MacVane points to a CRE called NDM-1, a gene carried by some strains of bacteria, which is resistant to even the last resort antibiotics, like carbapenems. 

“There are no current antibiotics to combat bacteria that have the NDM-1 gene, and this makes it potentially extremely dangerous,” he said.

NDM-1 stands for New Delhi metallo-ß-lactamase-1. It was first seen in 2008 in India. By 2010, it reached the U.S., and by 2015, it had been detected in more than 70 countries worldwide. The WHO said the rise of NDM-1 could present a "doomsday scenario of a world without antibiotics."  

“Once MRSA was the big threat,” said Parks. “But a CRE can be resistant to just about everything we have.”

She paused. “There’s nothing quite as bone chilling as looking at a patient and saying, ‘I’m sorry. There are no antibiotics to treat this.’”

Dictionary page turned to superbug entry

Parks came to MUSC at the beginning of the year to join the Antimicrobial Stewardship Program that has been in existence since 2009. She was pleased with what she found: MUSC has a very low rate of CREs. “The unique thing about MUSC is that we actually have a phenomenally low rate of these super-resistant organisms.” 

She feels that through a strong stewardship program, MUSC can make greater strides in judiciously using the antimicrobials that are left, which could delay the evolution of resistant bacteria. Already, the stewardship team has been able to reduce resistance to the drug Ciprofloxacin. 

“That’s important. We’re not quite at the very end — we can still slow this process. But we need to get the most mileage we can out of the antimicrobials that remain. That’s the point of stewardship,” she said. “To be proactive and continue to guard the unnecessary use of our antimicrobials in order to preserve the rate of low CREs.”

Will bugs stay one step ahead? 

Another big problem is there are few innovative new antibiotics in Big Pharma’s pipeline. Developing antimicrobials is not a lucrative endeavor, and it’s very time-intensive, Parks said.  

“Development and production has really has slowed tremendously over the last 20 years. You don’t take antibiotics daily for the rest of your life, like you do with Lipitor or Norvasc. It’s perhaps a week or two. For all the time and money that goes into developing a new antibiotic, the return on investment really isn’t there. As a result, they are not compelled to invest their dollars there.” 

In 2014, a presidential task force for science and technology determined that emerging antimicrobial resistance was not only a public health threat but a threat to the U.S. economy. 

“As a result, they outlined what we needed to do as a nation to prevent this from becoming a true catastrophe. From that, the Joint Commission made antimicrobial stewardship mandatory for all acute and now subacute hospitals and nursing homes. That’s a good thing.”   

Parks’ recruitment is an effort to ensure that antimicrobial stewardship continues to grow and develop. She said MUSC has a top-notch stewardship program, but it could be a lot more. It’s understaffed, she said. 

“The effort at this point as an institution is to develop a more robust stewardship initiative. The subject needs more awareness. Most people don’t even know infectious disease doctors exist. We need at least two more pharmacists. The pharmacists are the linchpin of the whole program. A specially trained pharmacist, like Shawn MacVane, who has done a fellowship in infectious disease, is invaluable. They monitor hospitalwide use of antimicrobials, making sure the correct ones are being used.”

Melroy agreed. “Shawn and his colleagues are not in the daily lens of the staff and patients at MUSC, but they are guardian angels in the background. They are experts in understanding susceptibility and resistance patterns. They are helping providers and patients improve our antibiotic utilization. They are curbing the threat by making sure patients are on the most appropriate therapy. Patients don’t know what the risks are with these agents, so our staff helps ensure their safety.”

Parks and MacVane also work closely with Lisa Steed, Ph.D., director of diagnostic microbiology in the Department of Pathology and Laboratory Medicine. Parks praised the rapid diagnostics capabilities at MUSC.

“We have cutting-edge technology that helps to identify problem organisms generally about 24 hours sooner than you would if you had to use standard culture methods. And, we have Dr. Steed. She’s incredibly sharp, and she’s passionate about this work. You have to have the passion to make any of this work.”   

She bottom-lines the looming problem — it’s all about antimicrobial stewardship. 

“At the end of the day,” Parks said, “we’re all potential patients. Every single one of us who works and practices here are patients, and nobody wants an infection like a CRE. What we can do is be good stewards of our remaining antibiotics, put effective systems in place and make sound decisions. Antibiotics are really a treasure; one we have too long taken for granted.”