Worrisome antimicrobial resistance

from my story at Leader’s Edge Magazine

Several years ago, Aetna uncovered a major problem among more than 1,000 doctors in its network

The large insurance carrier referred to the physicians by a nickname that summed up the problem in a single word: “superprescribers.”

Tapping into its data, Aetna found that nearly 1,500 doctors inappropriately prescribed antibiotics for bronchitis at least half the time. Aetna repeatedly warned doctors not to prescribe antibiotics, which target bacterial infections, to combat bronchitis, a viral infection. In other words, the medicine was useless against the infection. Despite those admonitions, Aetna says at least 432 doctors continued to prescribe the wrong drugs.

Too often, says Dr. Dan Knecht, Aetna’s vice president for clinical strategy and policy, “it’s easier for physicians to prescribe antibiotics.” When antibiotics are overprescribed, however, they might not be effective against infections or illnesses they once easily overmatched.

Around the world, bacteria are fighting back and winning against antibiotics. The occurrence of antimicrobial resistance, or AMR—bacteria that are resistant to multiple antibiotics—is growing. That growth has been spurred by the overuse—and improper use—of antibiotics, which has enabled bacteria to build defenses against them. The result is drug-resistant infections in both animals and people.

At least two million Americans contract antimicrobial resistant infections each year, and 23,000 of those people die, according to the Centers for Disease Control and Prevention. Drug-resistant infections are said to account for 700,000 deaths annually and are projected to cause 10 million deaths by 2050 and cumulatively result in trillions of dollars in losses.

“It has become one of the great global public health challenges of the century,” says Dr. Joan Butterton, associate vice president and senior director in the Department of Clinical Pharmacology at Merck Research Laboratories. “The bacteria are smarter than we are.” Merck touts itself as one of the few large pharmaceutical companies in the country to be developing new antibiotics. It has helped initiate the Study for Monitoring Antimicrobial Resistance Trends (SMART), a large AMR surveillance study involving 63 countries that is identifying resistance patterns.

The antimicrobial resistance risk has cascaded across the population landscape. And business is far from immune.

“I believe that AMR/AMU [antimicrobial resistance/antimicrobial use] is a business risk that can have strategic, financial, physical, operational and reputational losses associated with it,” says Melissa Hersh, a Washington, D.C.-based risk analyst and consultant. She and other experts believe the threats posed by AMR are dangerous enough to be considered in the same breath as cyber threats.

“I would say it’s high up on the list of corporate concerns,” says Joan Buckle, a principal and consulting actuary in London for Seattle-based Milliman, an international actuarial and consulting firm. “It’s probably not high yet on the list of public concerns. It’s reasonable that big global insurers are informing their clients, but I don’t know how far down the chain it is. If it’s a local entity or national, it’s not on the agenda yet.”It has become one of the great global public health challenges of the century. The bacteria are smarter than we are.DR. JOAN BUTTERTON, ASSOCIATE VP AND SENIOR DIRECTOR, DEPARTMENT OF CLINICAL PHARMACOLOGY, MERCK RESEARCH LABORATORIES

As insurers purchase reinsurance to mitigate risk, AMR is a strategic focus, according to Yommy Chiu, vice president for life and health R&D for Zurich-based Swiss Re. Within the past year, the company held a forum about the impact of AMR. “Insurers across different product lines are at risk of being exposed to greater losses because of increasing AMR,” Chiu says. “They are starting to understand what an increased risk of AMR means for them. For example, what if you’re in the livestock business and the antibiotics you are reliant on to keep your livestock healthy become no longer effective? Or what if, in the health setting, a patient develops AMR to a treatment and therefore incurs higher medical costs because of that?”

“Risk issues—agricultural biosecurity, including antimicrobial resistance, and cyber and information risk—are seemingly unrelated at face value but are juggernauts that provide an opportunity for the insurance industry to pivot towards agility and resilience,” Hersh says. “While insurance is typically reactive versus proactive in its constitution, there is a need and opportunity for this industry to reevaluate its stance with respect to risk prevention and mitigation.”INSURANCE-LIKE MODEL

The lack of financial incentives associated with developing novel antibiotics has resulted in limited innovation in the space revolving around antimicrobial resistance, though it is critically needed, says Joan Buckle, a principal and consulting actuary for Milliman.

Milliman has issued a paper based on a study by Buckle indicating the principles of insurance may be applied to structure reimbursement models for novel antibiotics and ultimately stimulate innovation while offering financial protection to drug manufacturers.

One scenario discussed with Leader’s Edge involves the drug manufacturer in an insurer-like role and a health system (or other entity wanting access to novel antibiotics) in the policyholder role. The two would enter into a contract that would require the policyholder to make predetermined payments to the manufacturer to develop new antibiotics. The payments would be based on expected utilization of the drug and cost of resistance. Importantly, the guaranteed income is not based on volumes sold, Buckle says, thus removing a monetary incentive to flood the market with the drug, which leads to overprescribing.

Under this scenario, claims are the amount of the new antibiotic released into the market. The less antibiotic released (i.e., the lower the claims), the better it is for the manufacturer (the insurer), as they are protected from underutilization by the premium payment. The higher the claims (more antibiotic released into the market), the more risk the insurer (manufacturer) must absorb. Guidelines could also be put in place to prevent a manufacturer from withholding the drug inappropriately.

The policyholder thus incentivizes new antibiotic development and gains some control over the amount released into the market.

Government Response

How can insurers engage proactively in addressing AMR risk? Government organizations and advocacy groups that are pushing for antimicrobial stewardship programs to limit the use of antibiotics believe insurers can play a key role in tracking the use of medications and providing data to providers in efforts to roll back usage.

In a statement to Leader’s Edge, the Food and Drug Administration said it’s in discussion with other federal agencies, including the Centers for Medicare & Medicaid Services, to “explore the means for reimbursement of certain new antibacterial drugs that meet critical patient and public health needs.”

“Insurers are definitely among the stakeholders who are an important part of our plan for combating antibiotic resistance,” the agency said. “We think the financing and payment side is a very important piece of the puzzle that needs to be addressed to help ensure a robust drug development pipeline.”

In August, CMS issued a final rule on Medicare payment policies for hospitals that also focuses on antimicrobial resistance. CMS says it has revised Medicare payment policies that can open the door for more innovative medications to address antimicrobial resistance. The new formula reverses a previous mandate that officials say restricted payment for new antibiotics in hospitals. CMS officials blamed the former standard for the financial collapse of a drug maker despite FDA approval of the manufacturer’s proposed treatment for complicated urinary tract infections.

“AMR is an increasingly serious threat to America’s seniors, including Medicare beneficiaries,” CMS said in a statement. “Without effective new antibiotics, patients will have fewer choices to treat drug-resistant infections, including those related to surgery and cancer-therapy. AMR results in hundreds of thousands of additional hospital days for Medicare beneficiaries, causing billions in unnecessary health care expenses,” CMS said.

Calling antimicrobial stewardship programs “critical,” the agency said its plans are not only to reinforce payment reform effectiveness but also to help move clinicians “towards the appropriate use of new antibiotics tailored to each patient.”

Moving clinicians toward changing prescribing practices—and consumers toward acceptance of using fewer antibiotics—are behavior changes in which the insurance community could also be involved, Hersh says.

Ultimately, “insurers can sound alarm bells and collaborate with health and policy experts to see how to create behavioral changes using both incentives and disincentives,” Hersh says. She concedes, however, that the insurance community is reluctant to “stick their necks out and raise a risk issue without having a mitigation solution or offering.”

Checking Doctors’ Pulse

One of the problems with burgeoning antibiotic resistance is that, whenever people want antibiotics, physicians are inclined to prescribe them. One troublesome setting for inappropriate prescribing is in outpatient visits. About 44% of outpatient antibiotic prescriptions in the United States target conditions such as sinus infections and viral upper respiratory infections, including asthma, allergies and pneumonia, according to the Pew Charitable Trust. Yet half those prescriptions were unnecessary, because viral illnesses do not respond to antibiotics, Pew says. A White House national action plan goal, released in 2015, focused on reducing inappropriate outpatient antibiotic use by 50% in 2020, according to Pew.

“It is estimated that up to half of antibiotic use in humans and much of antibiotic use in animals is unnecessary and inappropriate and makes everyone feel less safe,” says Dr. Ronald Leopold, chief medical officer for Lockton Benefits Services, in Kansas City, Missouri. “Stopping even some of the inappropriate and unnecessary use of antibiotics in people would greatly help in winding down the spread of resistant bacteria.”

Leopold says while there have been training and education efforts to mitigate antimicrobial misuse, government, nonprofit and other organizations are stepping up their tracking of provider prescription patterns and employing quality-management programs with prescription tracking being the metric.

Insurers are among those keeping watch on doctors’ prescribing practices. For the past three years, Aetna has sent 4,500 letters to providers urging them to refrain from using antibiotics when not necessary. Some letters admonish physicians for prescribing antibiotics for acute bronchitis. Other letters praise physician “champions” who never prescribe antibiotics for these conditions, Knecht says.

The approach led to a drop in antibiotic use among Aetna member patients by one-third, from 27% in 2014 to 18% in 2016.

Aetna says it is collaborating with the CDC to focus on states with the highest rates of overprescription. The company believes its actions can make a significant difference in the fight against antibiotic resistance while also cutting unnecessary healthcare spending. Acute bronchitis was chosen, Knecht says, because “it’s common and antibiotics shouldn’t be prescribed, but physicians have substantially overprescribed for this viral condition.”

Many insurance brokers seem to have taken only tentative steps to evaluate the antimicrobial issue, but Leopold says they can take significant steps to thwart antimicrobial problems. They can identify what health plan administrators and carriers are doing regarding tracking, monitoring or intervening in antibiotic usage.

Among other things, brokers can “flag” providers who have been identified as misusers or overusers of antibiotics, as Aetna does, he says. When that happens, cited providers might receive additional levels of file review, attend mandatory training and education, or face financial consequences or penalties, Leopold says. Brokers can provide independent claims data reviews of antibiotic use by providers for a client and monitor hospital-based infection rates for an employer’s health plan, Leopold says. Brokers can also help ensure that identified providers who seem to prescribe too many antibiotics receive appropriate intervention and that their activity is monitored. They also can educate employers about the issue and devise appropriate communication strategies for employees and plan members.

“It’s alarming to see that the rate of antibiotic-resistant infections has doubled since 2002 and spending to treat patients is 165% higher than for those without resistant bacteria,” says Dr. Shealynn Buck, chief medical officer at Lockton Dunning Benefits. “Insurers and pharmacy benefit managers have an important role in monitoring and ensuring provider adherence to quality standards for antibiotic prescribing.”

An opportunity for monitoring inappropriate antimicrobial use is in the outpatient setting, including physicians’ offices, telemedicine, urgent care centers and emergency departments, Buck says. Most antibiotic prescriptions, she says, are written in outpatient settings.

Brokers can partner with medical and pharmacy administrators on behalf of employers to include antibiotic stewardship measures in annual health plan reporting, Buck says. For employers who directly contract with providers, “brokers can facilitate a provider audit and ongoing review process.” Their evaluations can be based on the 2018 Quality Improvement Organization’s A Field Guide to Antibiotic Stewardship in Outpatient Settings, she says. That guide provides practice advice for reducing and monitoring inappropriate antibiotic use, Buck adds.

Employers can also play a significant role in antimicrobial resistance issues. “Employers can help raise awareness and educate their health plan members about appropriate antibiotic use so they understand why they don’t need an antibiotic and can make the right choice when they are sick,” Buck says. Generally, she adds, “providers are put in a tough spot when patients demand a prescription and then give the provider a poor rating if they don’t get what they want.”

Urgent Care Consumers

Dr. Cindy Liu, chief medical officer at George Washington University and the Antibiotic Resistance Center at the Milken Institute School of Public Health at GWU in Washington, D.C., says urgent care centers, which are growing rapidly as the go-to place for patients who don’t want to go to the emergency room, reflect the problem of patients being treated with antibiotics when they shouldn’t be. Often, the patients have a co-pay with an insurance company for their urgent care visits.

Many urgent care centers treat a disproportionately high number of coughs, earaches and sore throats that may be the result of viral, not bacterial, infections. “Often in the urgent care setting, patients are treated as consumers,” Liu says.

On the other side, the urgent care practice is often seen more like a business than a doctor’s office. The urgent care centers want to optimize their visits, want shorter visits, and aim for quicker turnaround time, Liu says. “There’s no time to build that relationship and educate the patient. They may also be at the mercy of patient satisfaction. And patients want an antibiotic.”

A study by Pew and CDC found nearly half of patients at urgent care and other healthcare clinics diagnosed with acute respiratory conditions were given antibiotic prescriptions. “We know that often patients demand antibiotics from their care providers even if a prescription is not warranted and, if they don’t receive it, they will search out someone who will give them the prescription,” Liu said in a statement.

To reduce antimicrobial use at urgent care centers, the Antibiotic Resistance Action Center and the Urgent Care Association, which represents urgent care centers, teamed up to develop patient education programs, implement training for healthcare workers, and collect data on antibiotic prescribing.It is estimated that up to half of antibiotic use in humans and much of antibiotic use in animals is unnecessary and inappropriate and makes everyone feel less safe.DR. RONALD LEOPOLD, CHIEF MEDICAL OFFICER, LOCKTON BENEFITS SERVICES

Lack of Data

A major gap in combating AMR involves the lack of data—not only the wide range of drugs impacted but also the ability to calculate potential losses from widespread antimicrobial resistance impacting human and animal life, researchers say.

“I believe that reinsurers and insurers should be using data analytics to assess the current state of claims related to AMR or AMR-associated losses across agricultural, human and life policies,” Hersh says. “More data are needed to make better decisions. Such data should be compared to models that forecast loss and impacts if AMR goes unchecked. I think that on the organizational level the issue needs to be elevated to the C-Suite, as this is not an issue that pertains only to the risk management point of contact.” In that way, she says, it’s similar to cyber-security concerns.

Among the problems is a “lack of specificity of data,” Milliman’s Buckle says.

“There are disease registries of AMR in certain countries that are thorough survey data on what the level of drug resistance actually is. But it’s still very difficult to look at medical claims data to pick up a reasonably accurate prevalence rate” of a specific case of antimicrobial resistance, Buckle says. “If you are an insurer trying to quantify AMR and trying to understand the different contributors, the lack of data is going to be a problem.

“Medical claims data has poor coding of antibiotic resistance, and as a result, the prevalence of AMR is potentially understated if trying to measure. For example, medical claim information may contain information to indicate that a patient had pneumonia but potentially not that they also had antibiotic resistance.”

Hersh says in the agricultural sector, in particular, “there’s a need to collect more robust and reliable data related to the use of antimicrobials in animal production and their impact on public health.” That can be difficult, in part, because of the practice of illicit or even off-label use of antimicrobials related to animal farming, she says. “Healthcare providers and clinical epidemiologists need to cooperate with the agricultural industry as well as include patient questionnaires about food consumption,” Hersh says, “even if most people don’t know or care about food supply chains.”

Ultimately, Hersh says, the insurance issue may eventually not only affect health insurance claims but also property/casualty and general liability losses.

Infections, Infections

As each day goes by, there are more dreadful stories of bacteria and resultant infections gone amuck. People who are stricken with staphylococcus aureus, considered the most dangerous of the many common staphylococcal bacteria, can get skin infections, pneumonia, heart valve infections and bone infections. Staphylococcus is a group of bacteria that has more than 30 types. It is estimated that 30% of the population carries staph on the skin or in the nose.

And people with MRSA (methicillin-resistant staphylococcus aureus) are 64% more likely to die than people with a non-resistant form of the infection, according to the World Health Organization. Escherichia coli (E. coli) is the leading cause of urinary tract infections and is becoming increasingly resistant to medications, according to the WHO. In 2016, 490,000 people developed multi-drug resistant TB around the world, and drug resistance is starting to “complicate the fight” against HIV and malaria, according to the WHO.

Earlier this year, a woman in her 70s died in Reno, Nevada, after contracting a superbug that could fend off 26 different antibiotics—that’s an extreme example, but not so far-fetched for what may be ahead. Officials say surgery and cancer chemotherapy can also be threatened with drug resistance.

Full Circle

The current situation involving antibiotics is ironic. “Antibiotics are the most important health breakthrough of the 20th century,” Knecht, from Aetna, says. “Antibiotics certainly reduced illness and led to longer life. In the early part of the 18th century, people were dying in their 40s from pneumonia because of bacteria. Now the leading cause of death is heart disease and cancer. I cannot overstate the value that antibiotics bring to society.”

While antibiotics boomed and were the heart of fighting sickness, they became “a victim of their own success,” Knecht says. “It’s the perfect storm of overuse.”

Elderly residents are particularly prone to antimicrobial infections because of their vulnerability to drug-resistant infections and greater exposure to pathogens. As antimicrobial resistance builds, it gets harder to find new drugs. “Physicians who reach for another antimicrobial arrow are finding their quivers empty,” wrote Seema Verma, director of CMS, “with the exodus of large companies and the bankruptcy of small firms contributing to the diminishing pipeline of drug development.”

Indeed, many large pharmaceutical companies and startups have declined to work on antimicrobial resistance drugs, citing costs, both in time and money. Former FDA administrator Scott Gottlieb observed in a statement: “Large pharmaceutical companies have, for the most part, exited from antibiotic research. And while some small, venture-backed, start-up companies remain engaged, these companies are not as well-positioned to fund the larger confirmatory trials required for regulatory approval.” As large companies reduce their efforts, Gottlieb says, “the funding pool available for commercializing innovative projects is shrinking.”

Merck is one of the few pharmaceutical companies that continues to pursue research and develop new medicines and vaccines that prevent and treat bacterial infections, says Butterton, from Merck Research Laboratories. “We’re committed to antimicrobials. We are an infectious disease company,” Butterton says. “It’s part of our mission, and we recognize the incredible public health importance.” Since 2014, Merck has introduced two novel antibiotics to reduce the recurrence of Clostridium difficile infections in adults receiving antibacterial treatment. It is also working on other pharmaceutical products designed to fight antimicrobial resistance. Merck says it has collaborated with more than 1,100 hospitals throughout the world to implement AMR-related programs, including training 10,000 healthcare providers. Its animal health unit also is developing vaccines for various animal-related diseases.

Butterton concedes the path toward developing drugs in the fight against antimicrobial resistance is not easy. “It gets harder and harder, and we have put in a lot of capital risk for years without a guarantee of success,” she says. “Companies have a real hard time. They bring medicines to market and then go out of business.”

A Fight Not Over

Through various partnerships and mandated programs in health, major steps are being taken to reduce antibiotic resistance, such as in infection control within healthcare facilities, says Michael Craig, senior advisor for the antibiotic resistance coordination and strategy unit at CDC. “We have made big strides as a country in the past decade, such as with healthcare-associated infections, and making improvements with infection control,” Craig says.

Yet he concedes there is a long way to go. “It’s still not where it needs to be in terms of mortality or the number of resistant infections,” he says. “The patient population is sicker, and the challenges we face will continue to be great. It is something you need to be vigilant about. You can’t take the day off.”

Hersh says a holistic approach to vigilance must be practiced by everyone involved in the issue—from doctors and patients to insurers and regulators. Hersh recalls that years ago, when she was living in London, she felt sick and went to a hospital emergency department. As an asthmatic, Hersh was concerned she had pneumonia, but as a knowledgeable professional, she also wanted to know if her condition was bacterial or viral.

After checking her, a physician didn’t think it was bacterial. He offered her antibiotics anyway. “You can imagine the mouthful that the tired young doc received from me,” she says.ON THE FARM

In agriculture, antibiotics have provided farmers and ranchers with an important tool to help sick animals, leading to improved livestock productivity. But these drugs can also be transmitted to consumers through the animals’ meat and may also wash off into streams as runoff. Antimicrobials also have been used as pesticides.

In the United States, however, major efforts have been made to reduce the number of antimicrobials in agriculture, with much success, says Dr. Paul Plummer (DVM), director of the National Institute of Antimicrobial Resistance Research and Education, based at Iowa State University.

In 2015, the Food and Drug Administration amended the Animal Drug Availability Act of 1996, revising the veterinary feed directive (VFD) drugs section. A VFD drug is intended for use in animal feeds, and use of the VFD drug is permitted only under the professional supervision of a licensed veterinarian.

Under the revised rule, antibiotics for animals that also make up human medicine can no longer be used for growth promotion in cows, pigs, chickens or other food animals. And their remaining therapeutic uses must be done under the supervision of licensed veterinarians and cannot be purchased over the counter.

The FDA released data in December that shows “domestic sales and distribution of all medically important antimicrobials” intended for food-producing animals decreased by 33% between 2016 and 2017. The agency’s 2017 “Summary Report on Antimicrobials Sold or Distributed for Use in Food-Producing Animals” also showed that domestic sales and distribution of the antimicrobials decreased 41% from 2015, a peak year, and also decreased 28% since the first year of reported sales in 2009.

“The reduction in sales volume observed in 2016 and 2017 is an important indicator that ongoing efforts to support antimicrobial stewardship are having a significant impact,” the FDA said in a report.

Food producers also have embraced marketing and branding that “designates whether or not their products used hormones or antibiotics,” says Melissa Hersh, a Washington, D.C.-based risk analyst and consultant. “The food supply issue is gaining more traction” in getting the message across about antimicrobial resistance, Hersh says.

Similar to cyber breaches that can result in losses, economic or otherwise, the antimicrobial issues on the farm reveal “smaller farms or large-scale production has a role to play in mitigating the risk to their assets,” Hersh says.

Otherwise, Hersh and others say, antimicrobial resistance in agriculture could result in a ripple of supply-chain disruptions, as grain and feed producers also absorb consequences as livestock die.

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