By Kelly M. Pyrek
In recent months, the medical community has witnessed outbreaks of NDM-1, KPC and a new strain of Escherichia coli, underscoring the urgency of addressing antibiotic stewardship to save lives and billions of dollars in costs caused by antibiotic-resistant and antibiotic-susceptible pathogens.
A warning and a call to action are issued in a special supplement, Combating Antimicrobial Resistance: Policy Recommendations to Save Lives, in the May 2011 issue of Clinical Infectious Diseases: "Seven decades of medical advances enabled by antibiotics are now seriously threatened by the convergence of relentlessly rising antibiotic resistance and the alarming and ongoing withdrawal of most major pharmaceutical companies from the antibiotic market. Without effective antibiotics, diverse fields of medicine will be severely hampered, including surgery, the care of premature infants, cancer chemotherapy, care of the critically ill, and transplantation medicine, all of which are feasible only in the context of effective antibiotic therapy. Our ability to respond to national security threats (e.g., bioterrorism and pandemics) also is in serious jeopardy. Ultimately, the loss of effective antibiotics will result in a great increase in morbidity and mortality from infections."
It's a message that organizations such as the Infectious Diseases Society of America (IDSA) and numerous others, along with the Centers for Disease Control (CDC) and the World Health Organization (WHO), have been promulgating for years, but seems to be unheeded. Let's take a quick look at a few of the resistant organisms that are presenting a global challenge:
In 2009, the world was introduced to New Delhi metallo-beta-lactamase (NDM-1), a new enzyme produced by a few families of bacteria that allow these pathogens to resist the numerous antibiotics and antimicrobials in use today. Beta-lactamases break specific chemical bonds contained in antibiotics such as penicillins, cephalosporins and carbapenems, and in the case of NDM-1, it can defeat both older and newer groups of antibiotics, thus presenting a significant danger. Clinicians discovered that Klebsiella was the first bacteria to produce NDM-1 when a patient who had journeyed from India to England had an infection that did not respond to therapeutic treatment. Researchers studied the organism's genetic and antibiotic resistance mechanisms and thus discovered NDM-1 and its genetic source -- a plasmid called "blaNDM-1." Other bacteria families (Acinetobacter, Escherichia and Enterobacter) were since discovered to have this plasmid in their chromosomes, which meant they could also produce NDM-1. The media and the medical community quickly started calling NDM-1 a "superbug" (an organism resistant to two or more antibiotics) that set off initial alarm, and the world was watching the potential spread of the organisms intently -- cases popped up in a number of countries, including the U.S.
Klebsiella pneumoniae Carbapenemase (KPC)-producing organisms have been on the medical community's radar for a while. The organism gets its name from the carbapenemase enzyme first discovered in Klebsiella pneumoniae isolates but which can be produced by other organisms including Serratia spp., Enterobacter spp., E. coli and Salmonella enterica. These organisms are resistant to all penicillins, cephalosporins and carbapenems, and the spread of KPC-producing organisms in the community and in the hospital environment represents a serious infection control and therapeutic challenge.
Enterobacteriaceae bacteria cause a wide variety of healthcare-associated infections (HAIs), and enterobacteriaceae with resistance to at least three classes of antibiotics are known as carbapenem-resistant Enterobacteriaceae (CRE). CRE, first reported in the U.S. in 1999, are sometimes referred to as "KPC-producers" or "KPCs," in reference to an enzyme which inactivates the carbapenem antibiotics. KPCs have been found to have a mortality rate as high as 40 percent.
Superbugs: Under Attack?
In a media-saturated world, it's easy to think that we are under attack by superbugs. In reality, the fact is that yes, resistant organisms seem to be gaining the upper hand, but the medical community is not without the knowledge and interventions required to fight back. The first step, however, is to acknowledge that organisms are evolving quicker than the antibiotic pipeline can supply new drugs, and to be cognizant of the factors that exacerbate resistance issues.
"These new resistant organisms, such as CRE, do represent a new phenomenon, which is the "untreatable" pathogen," says Arjun Srinivasan, MD, a commander in the U.S. Public Health Service and associate director for Healthcare Associated Infection Prevention Programs within the Division of Healthcare Quality Promotion at the CDC. "We have been dealing with methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococci (VRE), two pathogens that trigger lots of infections that are difficult to treat. Fortunately, we have had antibiotics to treat them, and especially for MRSA, we have had some new antibiotics that have come out in the last few years. The big change that I see is that we are now encountering organisms for which we have no good treatments, and in some situations we have no treatments at all. There are strains of CRE that are truly resistant to all antibiotics, and unlike MRSA where we had the luxury of having new antibiotics that were or had come on the market recently, for CRE we don't really have anything that's coming any time soon. To me, that combination of circumstances is a clarion call about a new generation of resistant organisms that pose a significant threat to those of us living in a post-antibiotic era. CRE are different than what we've encountered in the past and I think there is a different level of concern about these organisms; at the same time I think a lot of hype has been generated, particularly surrounding NDM-1, producing a lot of fear that was not informative or productive."
These aforementioned organisms present the greatest risk to patients who receive long courses of broad-spectrum antibiotics as well as patients with prolonged hospital stays, or have invasive devices such as ventilators or intravenous catheters, so that is why it is so critical that antibiotic stewardship be exercised strenuously. According to the CDC guidance on MDROs, "Once MDROs are introduced into a healthcare setting, transmission and persistence of the resistant strain is determined by the availability of vulnerable patients, selective pressure exerted by antimicrobial use, increased potential for transmission from larger numbers of colonized or infected patients ("colonization pressure") and the impact of implementation and adherence to prevention efforts." Because these organisms are easy to transfer from patient to patient and the infections they cause are very difficult to treat, diligent attention to infection control measures and contact precautions is paramount to prevention. Some studies have shown that effective strategies to control the spread of organisms such as KPCs include performing active surveillance, cohorting KPC-colonized and KPC-infected patients, assigning dedicated nursing staff to cohort units, and intensifying hand hygiene and environmental cleaning.
In a sense, KPCs and other emerging resistant organisms are similar to the less exotic hospital pathogens, MRSA and VRE, in that proven prevention and control strategies already exist. The guidance document, Management of Multidrug-Resistant Organisms In Healthcare Settings, (2006), outlines strategies and practices to prevent the transmission of MRSA, VRE, and other MDROs, especially hand hygiene, use of contact precautions, and environmental cleaning.
"There are things that we must do in any healthcare setting that are of universal benefit," says Srinivasan. "We must wash our hands when we need to. We must follow recommended contact precautions -- if there's a sign on the door that says 'Wear gowns and gloves,' we have to do that. We must clean the environment and the equipment properly. We must do all of these things and more 100 percent of the time and we have to do them properly. We also must develop the systems that will allow us to do that, and those are measures that will work against Acinetobacter and MRSA, and they will help with CRE."
Srinivasan continues, "At the same time, each facility must be aware of and monitor the resistant organisms that are of particular importance in their hospital. Every facility must monitor the resistance levels they see in their area, working with their clinical microbiology lab to know what the specific pathogen-related challenges are. Then they must consider that if Acinetobacter is a particular problem for them, they know that environmental cleaning is going to be of great importance to prevention -- and are they doing the job that they need to do. For CRE, one of the issues has been the problem of the unrecognized carrier patient -- the colonized patient -- and that some additional strategies such as active surveillance may be required to identify them. Facilities must implement all of these basic measures, they must monitor what they are seeing, and then they must make adjustments based on what they are seeing locally -- there may be measures that need reinforcement or measures that must be added."
Strategies to address MDROs are being promulgated by a number of organizations, including the CDC's Get Smart for Healthcare campaign, which focuses on strategies to help hospitals and other inpatient facilities implement interventions to improve antibiotic use. Get Smart for Healthcare studies indicate that nearly 50 percent of antimicrobial use in hospitals is unnecessary or inappropriate. There is no doubt that this overuse of antibiotics is contributing to the growing challenges posed by Clostridium difficile and other antibiotic-resistant bacteria in many hospitals. However, studies also demonstrate that improving the use of antibiotics in hospitals can not only help reduce rates of Clostridium difficile infection and antibiotic resistance, but can also improve individual patient outcomes, all while saving hundreds of thousands of dollars in healthcare costs. Get Smart for Healthcare is a CDC campaign focused on improving antibiotic use in inpatient healthcare facilities, starting with hospitals and then expanding to long-term care facilities.
Likewise, the CDC's MDRO guideline emphasizes as control or eradication measures the following: administrative support, judicious use of antimicrobials, surveillance (routine and enhanced), standard and contact precautions, environmental measures, education and decolonization. These measures are practices with which healthcare professionals are familiar. Hence, the knowledge is out there, but adoption of these practices is not as swift as public health experts would hope for. And while there are many unknowns left to discover, Srinivasan says waiting on the research to catch up to the problem is potentially foolish.
"I think you can make the categorical statement for anything in science or medicine that more research will always improve our understanding of how to approach a given problem," Srinivasan explains. "Of course for CRE, there are things we don't know -- we don't know a lot about the basic mechanisms of how the bacteria become resistant and how that resistance might be transferred between different organisms. We could use better strategies for the prevention of the development of these organisms as well as for the prevention of transmission. At the same time, I will argue that we already have the tools we need to do a very good job of preventing the development and transmission of CRE. I don't think we should let our need for more and new and better data stop us from implementing the things we know are effective. We know what works and what we need to do now is actually do it."
Srinivasan continues, "One of the areas we really need to focus our efforts on is to figure out better ways to approach resistant organisms, not just at an individual facility level, but within the community -- and this is something that the CDC and other partners have been working on. We know that the patients who have these drug-resistant organisms move between many types of facilities in our communities. They go from an acute-care hospital to maybe a long-term acute-care hospital and then to a long-term care facility before they go home and maybe get home care for a while. What we have seen in some of these situations is a lack of good communication between the facilities about the patient being colonized or infected with a resistant organism, and that has to change. It's been wonderful to see in the U.S. the growing role of local and state health departments in preventing HAIs. When you think about the group that would be ideal to coordinate this community-level or inter-facility approach to controlling infection, it is the local or state public health department that interacts with all these facilities."
Srinivasan urges practitioners to take an offensive, not defensive, approach to combating MDROs. "I think there's a temptation sometimes to feel helpless and to say, 'Well, until we have new antibiotics there's really nothing we can do.' And that's absolutely not true. There is a lot we can do today that has been demonstrated to be very effective. We must improve how we use antibiotics, and we must do everything we can to reduce the selective pressure that favors the development of these highly resistant organisms. The more we can do to improve the use of antibiotics in our hospitals, the longer we will have to maintain the effectiveness of our current antibiotics. That is something I think we don't do as well as we should. Many studies have shown that roughly one-third of the antibiotics we are using are used unnecessarily or ineffectively."
Srinivasan adds, "The other critical thing is preventing the spread of the organisms when they do develop, and that calls on us to implement the infection control measures we know work. Both of these imperatives are things we know how to do now. I would argue that the problem is not the knowledge gap, it's the implementation gap. We have to get people to do the things we know work, and it shouldn't stop us from looking for better ways to do all of these things. Nor should it stop us from trying to develop new drugs, but in the meantime, we must take action now. And we must have a coordinated, public health-based prevention strategy within a region to tackle these tough problems."
It's a tall order, but one which Srinivasan says is critical to the mission of upholding patient safety. "Patients in our healthcare facilities are sicker than they have ever been, which means the care we provide is more complicated than it's ever been," he says. "Hospitals are filled to capacity and healthcare providers are very busy getting more done in less time. While all of those factors are real and very difficult, we must figure out how we can fix or adjust the system to address these challenges. Patients won't -- and shouldn't -- accept care that is less safe simply because we are dealing with more complex issues -- that's no reason for care to be any less safe. That calls upon us as providers and as public health officials to work together to figure out how to provide care that is safe and optimal within the context of the challenges we face."
Combating Antimicrobial Resistance: Policy Recommendations to Save Lives. Clin Infect Dis. 52 (suppl 5): S397-S428. May 2011.
Management of Multidrug-Resistant Organisms In Healthcare Settings, 2006. Healthcare Infection Control Practices Advisory Committee (HICPAC), Centers for Disease Control and Prevention.
IDSA Recommendations for Addressing Resistance
In the aforementioned supplement in Clinical Infectious Diseases, the IDSA makes recommendations about how best to address the synergistic crises of rising rates of antibiotic resistance and waning approvals of new antibiotics:
- Adopt economic incentives and support for other collaborative mechanisms to address the market failure of antibiotics, including establishing new public-private partnerships to strengthen to traditional industry R&D for critically needed antimicrobial drugs.
- Create value-based reimbursement strategies that encourage antibiotic and related diagnostics development.
- Establish a panel of experts to document and regularly revise a list of priority pathogens or infections that have resulted or likely will result in an area of significant unmet medical need, and toward which adopted economic incentives should be targeted. The panel should include representatives from government agencies, academic and private infectious disease specialists, and public health experts.
- Take new regulatory approaches to facilitate antimicrobial development and approval.
- Enhance existing antimicrobial resistance surveillance systems.
- Strengthen activities to prevent and control antimicrobial resistance, including enhancing antimicrobial stewardship.
- Make significant investments in antimicrobial-focused research
-Boost investment in rapid diagnostics R&D and integration into clinical practice.
- Eliminate non-judicious antibiotic use in animals, plants and marine environments.