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Bugs Without Borders: The Global Challenge of MDROs

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“The spread of the NDM1-Kp is an emerging public health threat, as increased globalization may result in a higher burden of these bacteria in Canada and other countries than previously recognized,” says lead researcher Christopher F. Lowe, MD. “Preventing the spread of this organism in hospitals is critical given the lack of effective antibiotics against NDM1-Kp.” Challenges in fighting the spread of NDM1-Kp include contacts who acquire the bacteria, but may initially have a low concentration of organisms and avoid detection, as well as the lack of an established gold standard to detect carbapenem-resistant organisms, which may have contributed to the negative screens. Although the isolation of NDM1-producing bacteria is currently a rare occurrence in healthcare settings, this cluster indicates the prevalence of these organisms is increasing in nonendemic regions, and prompt initiation of infection prevention and control practices is essential to prevent transmission.

Another pathogen of concern that has been making headlines is Carbapenem-resistant Enterobacteriaceae (CRE) including Klebsiella pneumoniae carbapenemase (KPC), which are associated with mortality rates of up to 50 percent. Since being reported in 2001, KPC have been transmitted widely throughout the United States. Recognizing this public health threat, in June 2012, the CDC has released a CRE toolkit which expands on 2009 CDC recommendations. The CDC Toolkit - Guidance for Control of Carbapenem-resistant Enterobacteriaceae (CRE) is available at: http://www.cdc.gov/hai/organisms/cre/index.html.

Experts Answer Back
"I think it's a much more challenging situation than it was 10 years ago," says Henry Chambers, MD, FIDSA, chair of IDSA’s Antimicrobial Resistance Committee. "There has been considerable effort at drug development directed against resistant Gram-positive organisms and that continues. Of course, Staphylococcus aureus strains remain at the forefront. Fortunately, Streptococcus pneumoniae has not become a major problem. Although VRE strains have become more common, there are drugs out there that are active against them. So I think we are in much better shape against Gram-positives than we were a decade ago. It is just the opposite for Gram-negative organisms -- I would say we are in worse shape and there is no white knight on the horizon for several reasons. There has been a large change in the marketplace regarding the economic feasibility of developing antibiotics with short courses of therapy as opposed to a drug that a lot of people take for life -- the expense of the development is very high and the difficulty of developing a drug that is active against Gram-negatives  is a more difficult task, biologically.  There are many more specific resistance mechanisms that must be overcome, plus there has been a preference for developing broader-spectrum drugs and that makes it difficult to find agents that cut across a number of multidrug-resistant pathogens."

Moving from a domestic, hospital-based perspective to a more global outlook, Edward Septimus, MD, FIDSA, a member of IDSA’s Antimicrobial Resistance Committee, acknowledges today's global society and points to NDM-1 as being an example of a pathogen shared easily between continents.

"NDM-1 kp originally came from India and Pakistan, facilitated by travel to the UK and rapidly transferring from the UK to other countries to the point where we now have cases in the United States," says Septimus. "As another example, CRE started in the Northeast and is now fairly widespread across the majority of states, and there are other metallo-betalactamases that are circulating. MRSA is very well known and fairly widespread; we do have some newer anti-infectives that are active against MRSA -- they may not be great drugs but they are drugs nevertheless. If you look at the multidrug-resistant Gram-negatives, and many of those are the ESKAPE pathogens -- our armamentarium to treat those pathogens is very limited, so in addition to increasing incidence, we also have fewer drugs to treat these and some of the drugs we have are not very effective. That goes for MDR Acinetobacter and MDR Pseudomonas.  EBSL-producing E. coli and Klebsiella are fairly widespread now, not just in hospitals and nursing homes but also in the community."

Antimicrobial Resistance
The World Health Organization (WHO) defines antimicrobial resistance (AR) as resistance of a microorganism to an antimicrobial medicine to which it was previously sensitive. Resistant organisms (they include bacteria, viruses and some parasites) are able to withstand attack by antimicrobial medicines, such as antibiotics, antivirals and antimalarials, so that standard treatments become ineffective and infections persist and may spread to others. AR is a consequence of the use, particularly the misuse, of antimicrobial medicines and develops when a microorganism mutates or acquires a resistance gene.
According to 2011 data from the Centers for Disease Control and Prevention, antibiotic resistance in the United States costs an estimated $20 billion a year in excess healthcare costs, $35 million in other societal costs and more than 8 million additional days that patients spend in the hospital.

The WHO says AR is a global concern because:
- Infections caused by resistant microorganisms often fail to respond to the standard treatment, resulting in prolonged illness and greater risk of death.
- AR hampers the control of infectious diseases.
- AR reduces the effectiveness of treatment because patients remain infectious for longer, thus potentially spreading resistant microorganisms to others.
- AR threatens a return to the pre-antibiotic era; many infectious diseases risk becoming uncontrollable and could derail the progress made toward reaching the targets of the health-related United Nations Millennium Development Goals set for 2015.
- AR increases the costs of healthcare; when infections become resistant to first-line medicines, more expensive therapies must be used. The longer duration of illness and treatment, often in hospitals, increases healthcare costs and the financial burden to families and societies.
- AR jeopardizes healthcare gains to society; the achievements of modern medicine are put at risk by AR -- without effective antimicrobials for care and prevention of infections, the success of treatments such as major surgery would be compromised.
- AR threatens health security, and damages trade and economies; the growth of global trade and travel allows resistant microorganisms to be spread rapidly to distant countries and continents.

Understanding how resistance develops is critical to knowing how to prevent it. As the NIAID explains, microbes' primary function is to reproduce, thrive, and spread quickly and efficiently. Therefore, microbes adapt to their environments and change in ways that ensure their survival. If something stops their ability to grow, such as an antimicrobial, genetic changes can occur that enable the microbe to survive. There are several ways this happens.

There are biological causes of resistance, including selective pressure. In the presence of an antimicrobial, microbes are either killed or, if they carry resistance genes, survive. These survivors will replicate, and their progeny will quickly become the dominant type throughout the microbial population.
Mutation can also trigger resistance. Most microbes reproduce by dividing every few hours, allowing them to evolve rapidly and adapt quickly to new environmental conditions. During replication, mutations arise and some of these mutations may help an individual microbe survive exposure to an antimicrobial. Gene transfer also plays a role, as microbes also may get genes from each other, including genes that make the microbe drug resistant.
Societal pressures also factor into the resistance equation. The use of antimicrobials, even when used appropriately, creates a selective pressure for resistant organisms. However, there are additional societal pressures that act to accelerate the increase of antimicrobial resistance. Inappropriate use of antimicrobials are a significant factor. Selection of resistant microorganisms is exacerbated by inappropriate use of antimicrobials. Sometimes healthcare providers will prescribe antimicrobials inappropriately, wishing to placate an insistent patient who has a viral infection or an as-yet undiagnosed condition.
Inadequate diagnostics is to blame as well. More often, healthcare providers must use incomplete or imperfect information to diagnose an infection and thus prescribe an antimicrobial just-in-case or prescribe a broad-spectrum antimicrobial when a specific antibiotic might be better. These situations contribute to selective pressure and accelerate antimicrobial resistance. Critically ill patients are more susceptible to infections and, thus, often require the aid of antimicrobials. However, the heavier use of antimicrobials in these patients can worsen the problem by selecting for antimicrobial-resistant microorganisms. The extensive use of antimicrobials and close contact among sick patients creates a fertile environment for the spread of antimicrobial-resistant bacteria. 

A Quick Word About the Pharmaceutical Pipeline
As Rice (2010) observes, "During the past decade, the need for new agents with activity against the multidrug-resistant gram-negative ESKAPE pathogens has become increasingly acute. Pathogens against which we truly have no effective treatment are now isolated routinely in some hospitals. However, by most accounts, the current antimicrobial development pipeline in large pharmaceutical companies is very limited. This limited pipeline is partly a result of significant consolidation within the industry during the past decade, as well as the fact that many persons in large pharmaceutical companies have decided that antibacterials are insufficiently profitable to justify the investment of seeking new drugs ... Perhaps the most important reason for the anemic development pipeline is that the search for new agents to treat ESKAPE pathogens promises to be very difficult. The multidrug resistance expressed by these pathogens owes as much to nonselective detoxification mechanisms as it does to the accumulation of individual resistance determinants. As a result, these mechanisms can be expected to offer a measure of protection against virtually any toxic substance discovered or created to inhibit bacterial growth. It is therefore very likely that creative and novel strategies will be necessary to identify effective new anti-infective therapy. Accordingly, it is time for all stakeholders—physicians, industry, governmental and nongovernmental research organizations, and patients—to collectively develop strategies to preserve the activity of current antimicrobial agents and to promote the development of new ones."

Surveillance, Stewardship and Prevention
No matter what pharmaceutical developments occur over the next decade, it's clear that evidence-based practices to prevent the spread of MDROs are more important than ever. As  Siegel, et al. (2006) note, "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 ... There is ample epidemiologic evidence to suggest that MDROs are carried from one person to another via the hands of HCP. Hands are easily contaminated during the process of care-giving or from contact with environmental surfaces in close proximity to the patient. Without adherence to published recommendations for hand hygiene and glove use, healthcare personnel are more likely to transmit MDROs to patients. Thus, strategies to increase and monitor adherence are important components of MDRO control programs." For recommendations from the guideline, Management of Multidrug-Resistant Organisms In Healthcare Settings, 2006, visit: http://www.cdc.gov/hicpac/mdro/mdro_0.html

At the same time that hospitals implement these interventions, institutions struggle with surveillance of MDROs. "Even with an aggressive surveillance program you still would miss some of these organisms simply because if they exist in low numbers among other organisms, how do you sort out the one in a million?" Chambers says. "I don't think organisms such as NDM-1 are being transmitted in hospitals in the U.S. What's happening in Pakistan and India is that they are everywhere; they are acquired in the community, people become colonized, and they are spread via travel to the point that areas become endemic."

Chambers adds, "California mandates that certain individuals be screened for MRSA on admission to the hospital. Our situation at San Francisco General  is unique in that we have such a high burden of community MRSA, it is not feasible for us to screen and isolate every patient who is MRSA colonized. Instead, we monitor hospital and community rates and the contribution of serious strains to infections, emphasize a more general approach of hand hygiene, and sometimes implement isolation for cases that have the potential to spread resistant organisms. We monitor our infection rates to see if transmission is occurring; we do this through molecular surveillance periodically and also following crude rates. And our MRSA rates have actually gone down."

Chambers says facilities can assess who might need more aggressive screening from an empirical point of view. "These kinds of infections caused by extensively resistant Gram-negatives are rare in the U.S. but the concern is they won't be rare for long. That's simply the history of every drug-resistant organism unless the selective pressure is removed. In terms of where the greatest concern lies, I think it is the organisms that we already know about and have trouble with, such as those with extended-spectrum beta-lactamases. I am a lot more worried about those because the burden of disease is so much greater and they are something we experience on a regular basis in terms of challenging the therapies we have to treat them. For example, E. coli -- the most common cause of urinary tract infections, and the enzyme that confers resistance to commonly used drugs such as advanced-generation cephalsporins -- are really not that much different than the enzymes that confer resistance to ampicillin and half of E. coli or more are ampicillin resistant. About 10 percent of strains are ESBL, and they tend to be resistant to other drug classes as well. So that's a real problem for which we have limited answers. You can use a carbapenem, but that's the end of the road right now for Gram-negatives."

Chambers emphasizes the need for getting back to basics. "Hospitals in the U.S. need to be vigilant and realize that standard infection control and prevention measures and antibiotic stewardship are pretty much all we have at this point because the drugs are not very effective. One benefit of good infection control practices is it doesn't matter what the pathogen is -- if you apply appropriate precautions and isolation and the mechanisms we have in hand, they are designed to be pathogen-general. It boils down to good handwashing and avoiding practices that cross-contaminate. That is still the major mechanism by which these MDROs are transmitted. The challenge of many of them is the contribution of the environment for some of these organisms -- it makes it all the more challenging to avoid cross-contamination."

Chambers acknowledges the current dialogue in the community about implementation, duration and discontinuation of contact precautions, as well as the debate surrounding the application of horizontal infection control measures (targeting pathogens broadly) versus vertical measures that only target a few specific pathogens. "Measures such as screening and isolation remain controversial in terms of their benefit," Chambers says. "I believe hospitals should engage in interventions that are effective against a broad range of pathogens.  It's very expensive and resource-intensive to target individual organisms so it is better to have a broadly applied program that is directed at transmission of all drug-resistant organisms. It gets us back to contact precautions and handwashing."

Septimus concurs, noting, "I am a big advocate of horizontal intervention because when we verify just one organism such as MRSA we disproportionately put our efforts against it. But if we put horizontal interventions into place, such as antimicrobial stewardship, we are more effective. We must also consider this issue of resistance across the continuum of care. One of the things I have stressed in the working groups is to do education and interventions on a community basis, not just in hospitals but in LTACHS and nursing homes. In addition we must also engage the primary care physicians who might be writing prescriptions for asymptomatic bacteriuria and viral upper respiratory infections -- we see a spike in prescriptions during the viral respiratory season and it has correlated to a spike in more resistant organisms.  We must tackle the issue of antimicrobial resistance by reducing misuse and overuse of antibiotics for all infections -- and not just the ESKAPE pathogens-- on a community-wide level, across the continuum of care."

One of the important ways to curb resistance is for hospitals to implement antimicrobial stewardship programs to promote awareness about antibiotic overuse. The Infectious Diseases Society of America (IDSA) has been a supporter of the CDC's annual “Get Smart About Antibiotics Week,” held every November to educate the public, healthcare providers and policymakers about the importance of using these lifesaving drugs wisely.

“Antibiotics have changed medicine as we know it, but too often, we take them for granted,” says IDSA president David A. Relman, MD, FIDSA. “If we do not act now to preserve this lifesaving resource and give antibiotics the respect they deserve, we face a return to a time when people died of common infections, and many medical advances we take for granted—like surgery, chemotherapy, and organ transplants—simply aren’t possible.”

IDSA has joined with the CDC and other national healthcare organizations to commit to principles, including encouraging the appropriate use of antibiotics, to conserve and replenish antibiotic resources. IDSA has also helped create a consensus document on antibiotic resistance (visit: http://cddep.org/sites/cddep.org/files/etc_consensus_statement.pdf0). IDSA has been sounding the alarm about antibiotic resistance for many years, highlighting the need for a multipronged approach to the crisis. While appropriate antibiotic use is a key part of the solution, another critical element is providing economic incentives that encourage antibiotic research and development, such as the Limited Population Antibacterial Drug (LPAD) pathway proposed by IDSA to streamline the development of antibiotics needed to treat the most serious, life-threatening infections. In addition, more advanced rapid diagnostic tools to unmask infections more quickly and accurately are needed. Finally, improvements in surveillance, data collection and immunization, and related research are in order.

“We are already seeing patients with bacterial infections resistant to every antibiotic we have left,” Relman says. “It will take all of us—consumers, healthcare providers, researchers, policymakers, industry, and others—to tackle this problem and ensure that effective and lifesaving antibiotics are available for future generations.”

A recent position paper from IDSA, the Society for Healthcare Epidemiology of America (SHEA), and Pediatric Infectious Diseases Society (PIDS) outlines measures necessary to improve the use and ensure the impact of antibiotics on emerging healthcare-associated infections. The paper on antimicrobial stewardship (AS) was published in the April 2012 issue of Infection Control and Hospital Epidemiology. National antimicrobial stewardship initiatives recommended in the paper include:
• Incorporate antimicrobial resistance and AS into the curriculum for healthcare professionals to ensure that practicing providers are knowledgeable in these areas.
• Collect data on antimicrobial use in both inpatient and outpatient settings. These data are critical to monitor antibiotic use and its relationship to antibiotic resistance.
• Monitor AS initiatives in ambulatory and outpatient healthcare settings. SHEA, IDSA and PIDS encourage federal agencies to fund pilot projects designed to develop and implement AS programs in these settings, including expanded use of electronic health records.
• Require health settings to implement AS programs through regulatory mechanisms. The authors recommend that the Centers for Medicare and Medicaid (CMS) require participating healthcare institutions to develop and implement AS programs to help optimize the use of antibiotics.
• Fill the knowledge gaps in our understanding of antibiotics resistance to increase our understanding of the transmission of resistance and assessing the impacting of clinical interventions.

"Although there has been a lot of discussion around antimicrobial resistance and stewardship, the translational, operational part of that is not well developed," cautions Septimus. "So we have examples of excellent programs but that is not necessarily translated to enough facilities to see an appreciable difference. The good news is there is a lot of attention in this area, and there is legislation. For example, in California there is a law that says every hospital must have a stewardship program -- it's not that well defined but it's a first step. Also, there is a new guidelines committee that is a combination of IDSA and SHEA that is now looking at the evidence around the implementation strategies, which is an important next step. We have guidelines for what antimicrobial stewardship should look like but we don't yet know the strategies that have the most evidence behind them. I think that we are making progress but it is happening very slowly. The primary stakeholders for stewardship are physicians, so what we are really talking about is changing physician behavior -- and that is very, very challenging."

Septimus is quick to emphasize that resistance is everyone's responsibility; although physicians play a major role in stewardship, a neglected stakeholder is the patient. "One of the groups we have to get through to besides healthcare professionals is patients, because they come in with the expectation that if they have some kind of upper respiratory illness they are going to receive an antibiotic.  Many physicians may not have the time to explain why they should not get an antibiotic. I think physicians feel pressured -- they are afraid their patient satisfaction scores will go down or they will lose patients altogether in a competitive market.  However, studies show that if the physician takes the time to explain to the patient why prescribing an antibiotic may be harmful, they retain patients maintain their satisfaction. Education of all stakeholders is necessary, but the physician has the power of the pen to write prescriptions, so we need to ensure they understand the ramifications. Right now in many situations there is no accountability for what we do. So unless we tackle this thorny issue, we will continue to have a very significant problem with resistance."

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Christopher F. Lowe, Julianne V. Kus, Natasha Salt, Sandra Callery, Lisa Louie, Mohammed A. Khan, Mary Vearncombe and Andrew E. Simor.” Infection Control and Hospital Epidemiology 34:1 (January 2013).

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