The Rising Threat of Antimicrobial Resistance

Clinical labs are on the front lines of the battle against drug-resistant bacteria and other organisms

By Sherry A. Dunbar, PhD, MBA

While the healthcare community watches anxiously as influenza, malaria, tuberculosis, and other disease outbreaks spread across new regions, the single greatest threat in infectious diseases today—and the common theme that unites these and so many other diseases—is drug resistance. A resurgence of organisms long thought to have been contained is now being driven by drug-resistant pathogens, many of which are adept at swapping the genes and plasmids that confer such resistance.

In the battle against drug-resistant bacteria and other organisms, diagnostic testing is already on the front lines. Clinical lab teams and commercial developers are working hard to stay one step ahead, but are challenged by rapidly evolving variants and other markers of resistance. Antimicrobial stewardship programs, considered among the most important and promising strategies for preventing the spread of drug resistance, rely heavily on high-quality diagnostics.

However, reversing the alarming trend of drug-resistant infections will require the concerted efforts of all stakeholders, from patients and physicians to clinical lab professionals and drug developers. Containing this global health threat will take every tool we have. This article looks at the current landscape of antibiotic resistance and its links to emerging infectious diseases, and considers how clinical labs and other groups can have a positive effect on efforts to bring an end to the rise of drug-resistant organisms.

The Epidemic

In a very short period, antibiotic resistance has gone from a relative rarity to a public health crisis. Research by the British government and the Wellcome Trust found that 700,000 people around the world die annually from drug-resistant infections.¹ At the current pace of increase, that number is expected to rise to 10 million by 2050, reducing the world’s gross domestic product by as much as 3.5%.

The World Health Organization published its first report on antimicrobial resistance in 2014, bringing attention to the seriousness of the situation (Table 1).^2,3 “Without urgent, coordinated action by many stakeholders, the world is headed for a postantibiotic era,” said Keiji Fukuda, WHO’s assistant director-general for health security, in a statement released with the report.⁴ “Unless we take significant actions to improve efforts to prevent infections and also change how we produce, prescribe, and use antibiotics, the world will lose more and more of these global public health goods, and the implications will be devastating.”

According to the WHO report, carbapenem-resistant Klebsiella pneumoniae—bacteria resistant to the last-resort treatment for this infection—can already be found in all regions of the world. Indeed, in some countries, more than half of K. pneumoniae cases are resistant to carbapenem antibiotics. Similarly, there are regions where fluoroquinolones, a class of antibiotics introduced in the 1980s, are now effective in fewer than half of patients with urinary tract infections brought on by Escherichia coli.

Another frightening trend is the rise of pathogens and parasites that are resistant to many different types of treatments. These multidrug-resistant infections are becoming more common and are proving increasingly difficult to overcome. In a national survey of infectious disease experts in 2011, the emerging infections network of the Infectious Diseases Society of America (IDSA) found that during the prior year 63% of respondents reported seeing at least one patient suffering a panresistant infection—that is, an infection resistant to all available antibiotic therapies.⁵

The biggest drug-resistant threats include carbapanem-resistant Enterobacteriaceae, Clostridium difficile, Enterococcus species of various types, methicillin-resistant Staphylococcus aureus (MRSA), Neisseria gonorrhoeae, and tuberculosis (Table 2).^6–8 In the United States alone, MRSA leads to more deaths each year than emphysema, HIV/AIDS, homicide, and Parkinson’s disease combined.⁷ According to WHO, drug resistance is becoming a concern in HIV and malaria too.

Compounding the problem is the continuing emergence of new threats. Scientists have recently identified the fungus Candida auris as one such problem. Discovered only 8 years ago in Japan, the pathogen has now spread around the world, and some strains are already resistant to all major classes of antifungal therapies.⁹ An ongoing outbreak in the United States has affected dozens of people, and the US Centers for Disease Control and Prevention (CDC) reports that fatality rates are as high as 60%.¹⁰ The agency has warned infectious diseases experts that C. auris is particularly challenging to identify accurately with conventional lab tests, making it even harder to get ahead of an outbreak.

Diagnostic Challenges

Antimicrobial-resistant pathogens present a real challenge for clinical labs. There is the standard task of having to identify the particular bacterium or other organism responsible for a patient’s infection—a task that is often far from straightforward—and now there’s the added complexity of determining as early as possible whether that organism is resistant to typical treatments. With traditional lab tests, it can take days to figure out a pathogen’s resistance profile. For patients facing serious infections, especially infections that are resistant to multiple drugs, that is simply too long. To select the treatment most likely to be effective, physicians need this information much sooner.

Adding to the challenge of spotting resistance markers is how rapidly these organisms evolve. We know that biomarkers associated with resistance to a certain drug may not be useful as the pathogen changes. How long these biomarkers serve as reliable signals of resistance is an open question in the diagnostic community.

As if that weren’t enough, clinical lab professionals must also deal with the complexity of coinfections. Particularly in regions with significant levels of endemic infections, such as malaria or tuberculosis, it is quite common to find patients infected with multiple bacteria or parasites. Most diagnostic tests focus on a single organism and are unable to detect cases of coinfection. Unfortunately, a positive result from such tests can mislead physicians into believing that the patient has only one infection, reducing the likelihood that they would pursue additional tests to find more potential issues.

Coinfection is a serious health problem on its own. Add in drug-resistant infections, and it’s clear that medical professionals need a complete view of a patient’s health to choose the best course of treatment. Even in cases where a primary infection is responsible for all of a patient’s symptoms, the presence of a secondary infection can lead to serious complications, particularly if that lower-grade infection happens to be resistant to the drug prescribed for the more obvious infection. An awareness of coinfection can provide a much-needed alert for cases where drug resistance is likely to be passed from one organism to another.

This situation necessitates faster, more flexible, and more comprehensive testing. The ability to rapidly introduce tests in clinical labs would help to address the challenge of evolving biomarkers and emerging drug resistance. It’s essential for developers of diagnostic platforms to consider speed and flexibility as key factors for their clinical lab users. By enabling developers in labs to design, validate, and implement new tests more quickly, they will be better equipped to stem the tide of resistance by reporting which treatments are most likely to be effective.

Also, clinical labs can make more use of multiplex testing to identify coinfections. Panel tests can be designed to include pathogens most likely to occur together, enabling laboratorians to run a single test and generate clinically important information that would be more difficult to reveal with individual assays. Taken together, testing platforms that offer increased speed, flexibility, and multiplexing ability will be essential for supporting clinical labs in the pursuit of identifying dangerous infections early, helping to avoid treatments that will not work and may have adverse long-term consequences.

Antimicrobial Stewardship

One of the most promising approaches for reducing infections and curbing outbreaks within hospitals has been the rise of antimicrobial stewardship programs. Often closely tied to an institution’s clinical laboratory, these wide-ranging programs incorporate standardized protocols, more sparing use of antibiotics, and other related measures designed to decrease inappropriate use of antimicrobial therapies.

At a recent meeting of the Michigan-based South Central Association for Clinical Microbiology (www.scacm.org), Ronald Reitenour, MT(ASCP), microbiology and HAZMAT coordinator at Riverview Health, presented results from an evaluation of molecular diagnostic platforms undertaken in part for the hospital’s antimicrobial stewardship program.¹¹ The goal was to deliver blood culture results more quickly, enabling physicians to select the most effective antibiotic, and to avoid unnecessary or irrelevant treatments that would only serve to increase the risk of developing drug-resistant microbes.

After comparing the Verigene system from Luminex, Austin, Texas, with another commercial system, Reitenour’s team chose to proceed with the former, in part because the Verigene assays enabled the lab to test for the most common pathogens and to choose among panel tests based on the Gram stain interpretation (Figure 1). Factors that the lab team considered most important for their antimicrobial stewardship program were speed and effectiveness. The Verigene system delivers results faster than standard lab tests, identifying pathogens as much as 22 hours sooner than culture, and providing information about likely resistance markers 48 hours ahead of conventional methods.

The lab’s evaluation showed that with these rapid results, there was a reduction in the duration of patient stays, lowering costs and decreasing the chances that patients would develop new infections during their time in the hospital. Such quick turnaround also makes it more likely that patients will get the right therapy sooner, alleviating pressure on hospital staff to start antimicrobial treatment before they know the cause of an illness (Figure 2).

These findings have been supported by data at many institutions seeking to use antimicrobial stewardship programs to prevent multidrug resistance. A study of more than 400 patients by pharmacy clinicians in 10 community hospitals in Florida found that nucleic acid-based Verigene blood culture tests for Gram-positive and Gram-negative pathogens reduced the average time to receive appropriate antibiotics by 18 hours, a 30% improvement.¹² The tests also contributed to shorter durations of antibiotic treatments for blood culture contaminants—a frequent red herring that leads to overuse of such therapies—and to lower rates of hospital readmission within 30 days of treatment.

Another Florida study, this one in the Orlando Health network, demonstrated that doctors were able to stop the use of unnecessary antibiotics 27 hours sooner, on average, with Verigene blood culture tests than with conventional methods.¹³ Shifting to the Verigene process cut the response time to less than half of the original 51 hours, and primarily affected patients who had received false-positive test results due to blood culture contamination.

Finally, studies of multidrug resistance incidents have shown that getting valuable information faster makes it possible for hospital teams to establish infection control barriers sooner, which is, of course, important for protecting other patients. At Drexel University and Hahnemann University Hospital, Philadelphia, clinicians found that rapid testing with the Verigene system reduced the average response time from nearly 29 hours to just over 4 hours.¹⁴ Such time savings would give hospital staff a full extra day for implementing precautions—time that could be critical for reining in the spread of resistant pathogens in a patient population (Figure 3).

Other Efforts

The fight against antimicrobial resistance will require advances from many other stakeholders. While few of these advances can be accomplished within the walls of clinical labs, encouraging the successful efforts of others is the responsibility of all medical professionals, including laboratorians.

More than anything, the community needs new therapy options. The organisms that threaten us are constantly evolving, and we will not get ahead of them without new antimicrobial treatments. Antibiotics may not be an appealing R&D investment for pharmaceutical companies if the resulting products are not expected to be as profitable as other therapies. Nevertheless, adding new weapons to the arsenal will be critical. Clinical lab members can do their part by raising awareness about the scope of the drug-resistance crisis among their colleagues in biotech and pharma settings.

In the meantime, the situation we face calls for improved education for physicians and other medical professionals about the appropriate prescription of antibiotics. Anyone who has ever gone to an urgent-care clinic complaining of cold symptoms knows how easy it is to walk out with a prescription for antibiotics. While the drugs may or may not affect the source of those symptoms, they may well have a pronounced effect on the development of drug resistance.

The overuse of antibiotics has played a large role in ushering in this health crisis, and we can do better. Clinical lab members, particularly those involved in antimicrobial stewardship programs, may find themselves in a perfect position to launch new education initiatives in their hospitals. Ideally, these initiatives will also be available for medical professionals who are not based at the hospital, but may be prescribing antibiotics at local clinics and other facilities.

The final piece of the puzzle is compliance, which is where patient education comes in. Too many patients stop taking their antibiotics before the full course is complete, a practice that can increase the risk of developing drug resistance as the residual infection establishes an environment for resistant bacteria to persist. We all have a responsibility to raise awareness of this issue with patients; nurses and physicians can spend more time explaining it, administrators can supply clear brochures, and clinical lab teams can find ways to include that information on reports that are seen by the patient.

Moving Forward

There will be no single solution to the growing crisis of antimicrobial resistance, but the many efforts in motion today are cause for hope. Clinical labs contribute significantly through implementing rapid molecular diagnostics and participating in antimicrobial stewardship programs. Being on the front lines, they also provide an invaluable service to the infectious disease community as a whole: spotting new cases and feeding that information back to agencies such as CDC, which in turn gather, analyze, and disseminate results for everyone. Patients, providers, and therapy developers also have important roles to play.

Without intervention from all of these sources, the fight against drug-resistant microbes looks quite bleak. Data from across the globe attest to the rapid spread of resistance, both geographically and across pathogen species. The rise of pan-resistant infections is a recent and alarming trend.

But as more labs, people, and organizations get involved in initiatives that raise awareness about incorrect use of antibiotics, improve the ability to detect drug-resistant microbes quickly, and boost the therapeutic arsenal with new antimicrobial drugs, there is real potential to address this global health threat—and save millions of lives in the process.

Sherry Dunbar, PhD, MBA, is senior director of global scientific affairs at Luminex. For further information contact CLP chief editor Steve Halasey via [email protected].

References

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