By Kelly M. Pyrek
Infectious disease experts say we are on the brink of losing our last line of defense against pathogenic microorganisms -- antibiotics and other antimicrobials -- unless the healthcare industry and policy-makers significantly improve efforts to preserve these drugs' effectiveness through antimicrobial stewardship initiatives. Antimicrobial agents, which include antibiotics and similar drugs, are effective, but microorganisms that cause infections can quickly develop resistance by a variety of mechanisms. The World Health Organization considers misuse and overuse of antimicrobials one of the top threats to human health, as it can lead to the emergence of multidrug-resistant organisms (MDROs), such as methicillin-resistant Staphylococcus aureus (MRSA). MDROs cause a significant proportion of serious healthcare-associated infections (HAIs) and are more difficult to treat because there are fewer and, in some cases, no antibiotics that will cure the infection. To illustrate, In October 2011, 562 infectious diseases physicians who are members of the Infectious Diseases Society of America (IDSA)’s Emerging Infections Network (EIN) responded to a survey about antibacterial-resistant infections. More than half (63 percent) of respondents reported caring for a patient with an infection resistant to all available antibacterial drugs in the prior year.
A recent report from the IDSA emphasizes that there are few candidate drugs in the pipeline that offer benefits over existing drugs and few drugs moving forward that will treat infections due to the so-called “ESKAPE” pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species), which currently cause the majority of U.S. hospital-acquired infections and effectively “escape” the effects of approved antibacterial drugs.
In a position paper, "The 10×'20 Initiative: Pursuing a Global Commitment to Develop 10 New Antibacterial Drugs by 2020," members of the IDSA's Antimicrobial Availability Task Force (Gilbert, et al., 2010) assert that "the antibiotic pipeline problem can be solved by bringing together global political, scientific, industry, economic, intellectual property, policy, medical and philanthropic leaders to develop creative incentives that will stimulate new antibacterial research and development (R&D). Our audacious but noble aim is the creation of a sustainable global antibacterial drug R&D enterprise with the power in the short-term to develop 10 new, safe and effective antibiotics by 2020."
To achieve this goal, several years ago the IDSA launched a collaboration, the “10 × '20” initiative, which has been endorsed by a number of professional medical and healthcare societies. Specifically, IDSA supports the development of 10 new systemic antibacterial drugs through the discovery of new drug classes as well as exploring possible new drugs from existing classes of antibiotics. Key to advancing antibacterial drug development is the concurrent need to advance the development of improved diagnostic tests specific to multidrug-resistant infections. As Gilbert, et al. (2010) note, "Global stakeholders can capitalize on each other's strengths to create a long-term, sustainable R&D infrastructure model that provides incentives for both antibacterial drugs and related diagnostic research enterprises. Success would be of immense benefit to the health of the citizens of the world. Furthermore, the sustained infrastructure created to achieve this goal would help to recreate the highly skilled scientific workforce that was lost over the past two decades as many companies abandoned antibacterial drug development. Microbial evolution causing antibiotic resistance is constant; our collective efforts at antibiotic discovery must be constant."
Another answer to the problem is the development of antimicrobial stewardship (AS) programs and interventions in as many healthcare facilities as possible; these programs help prescribers know when antibiotics are needed and what the best treatment choices are for a particular patient to help improve the use of these drugs. “Antibiotic stewardship is a critical component of providing quality care in any health setting,” says Neil Fishman, MD, SHEA past-president and an author of a new position paper from the Society for Healthcare Epidemiology of America (SHEA), Infectious Diseases Society of America (IDSA) and Pediatric Infectious Diseases Society (PIDS). “Effective stewardship will improve outcomes, conserve limited resources and limit emergence of resistance.”
“With few antibiotics in the pharmaceutical pipeline, we must take the necessary measures to preserve our current supply of antibiotics, and ensure that our children have access to these lifesaving medications.” says Christopher J. Harrison, MD, chair of the Pediatric Infectious Diseases Society’s Clinical Affairs Committee.
The position paper outlines measures necessary to improve the use and ensure the impact of antibiotics on emerging HAIs. Antimicrobial stewardship interventions have the potential to improve the quality of patient care throughout the United States, reduce healthcare costs associated with unnecessary treatments and help preserve the use of antibiotics for generations to come.
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 healthcare facilities to implement AS programs through regulatory mechanisms. The authors of the position paper 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.
“We’re not developing new drugs fast enough to keep up with the rise in drug-resistant infections,” says Ruth Lynfield, MD, chair of the Infectious Diseases Society of America’s National and Global Public Health Committee and state epidemiologist and medical director for the Minnesota Department of Health. "The issue is that we are seeing more and more pathogens that cause infections becoming resistant to the antibiotics that we have available to treat them. We now have infections in the U.S. that are resistant to all readily available, formerly effective antibiotics... It is becoming a more significant problem because we have had fewer new antibiotics being developed in recent years. It is much more financially viable for a pharmaceutical company to invest in a product that will be used every day for years rather than something that is used for a short period of time and has a limited lifespan because the bacteria may become resistant to the product. Therefore we really need to be very careful in the way we use the antibiotics that we have, in order to preserve these tools for as long as we can. We have for years used antibiotics without being mindful of the consequences and we are now paying the price."
To illustrate, in testimony before Congress in March, an official IDSA statement (IDSA, 2012) notes, "Ironically, as the number of patients succumbing to antibiotic-resistant infections rises, the number of new antibiotics in development is plummeting. Since IDSA’s 2009 report on the status of the antibacterial R&D pipeline (Boucher, 2009), only two new antibiotics have been approved in the U.S. and the number of new antibiotics approved annually continues to decline ... Antibiotic R&D poses unique scientific, regulatory, and economic challenges, which often makes antibiotic R&D riskier than R&D for other types of drugs. One company reports that over a 10-year period, it took 72 lead candidate antibiotic compounds in the early discovery phase to yield one FDA-approved product; other drug types only took 15 leads to yield an FDA approval. Antibiotics also provide less financial reward for companies as they are used for a short duration (i.e., often seven to 14 days), typically are priced low, and are encouraged to be held in reserve to protect against the development of drug resistance, rather than used widely as most other drugs are once approved."
Lynfield points to the recent rise of carbapenem-resistant Enterobacteriaceae (CRE). Currently, the most common type of carbapenemase in the U.S. is Klebsiella pneumoniae carbapenemase (KPC), and within the last several years, additional enzymes that confer resistance to carbapenems, known as metallo-beta-lactamases (MBL) have been detected in the U.S. "So not only do we have pathogens such as MRSA, creating treatment challenges, but now we have CRE," Lynfield says. "These bacteria have a plasmid that carries resistance to many classes of antibiotics and these resistant bacteria can be transmitted in healthcare settings. We are also seeing highly resistant infections occurring in people in the community -- people are familiar with community-associated MRSA but other highly resistant infections are also occurring including tuberculosis, pneumococcal and gonococcal infections."
Lynfield continues, "It is a big concern that we may return to a time when we don't have effective antibiotics. Antibiotics have plummeted death rates due to infections and have enabled advances in multiple fields of medicine including intensive care, transplant medicine and oncology. We don't want to be in a position where we don't have these powerful tools; this is what keeps infectious disease experts awake at night. It takes 10 years on average for new antibiotics to come down the pipeline, and because we are in a place right now where we are losing the effectiveness of our antibiotics, we have a huge problem."
Lynfield says she believes that antimicrobial stewardship strategies are key to immediately address this issue and protect the effectiveness of the next generation of antibiotics. "Since 1997, recommendations have been issued by IDSA and SHEA about antimicrobial stewardship, so this is not a new issue. Additional recommendations were issued in 2007 and in April 2012 a policy statement was published in Infection Control and Hospital Epidemiology. What it says is that we think there needs to be an antimicrobial stewardship program across the continuum of care, certainly in acute-care but also in long-term care, in ambulatory care, in dialysis centers, etc. As healthcare providers, we need to be good stewards of antibiotics. This involves promoting the selection of the optimal antibiotic, the right dose, the right duration, and the right route of administration. It's important to limit the selective pressure on bacterial populations that might select for resistant strains. What people need to realize is that when you administer an antibiotic, it doesn't just go to the infection site -- there is a systemic level of that antibiotic in the body so it impacts other bacteria. The bacteria that are susceptible to the antibiotic die and resistant bacteria survive. We know from studies, that people who have recently taken antibiotics do have a higher incidence of being colonized and of as well as being infected with resistant bacteria. Whenever an antibiotic is used there is an impact on the patient and on the community because we share our bacteria."
Antimicrobial stewardship programs are designed to help healthcare institutions achieve optimal clinical outcomes for patients as well as reduce costs, Lynfield says. "There is an increasing amount of data coming out about this, where facilities demonstrated that they saved money by implementing and maintaining an antimicrobial stewardship program. It makes good sense from an outcomes measurement perspective, from a patient safety and care improvement point of view, and we do have some data about cost savings."
The Role of Infection Preventionists in Antimicrobial Stewardship
Lynfield emphasizes the importance of infection preventionists' involvement in their facilities' antimicrobial stewardship programs. "The ideal antimicrobial stewardship program has a multidisciplinary team that includes a physician, a pharmacist, a clinical microbiologist and an infection preventionist. Infection preventionsts are critical to the team because they have a lot of interaction with healthcare providers and they are used to going into various units, teaching and assessing infection-related issues," she says. "They are very attuned to antimicrobial resistance issues and they can help measure the impact of an the antimicrobial stewardship program in their facility."
Lynfield's opinion is echoed by the authors of the aforementioned multi-society position paper:“The skills and knowledge each of these highly skilled professionals bring to a facility’s antimicrobial stewardship programs, when combined with other disciplines, can accelerate progress toward preventing emergence and cross transmission of MDROs. Antimicrobial stewardship programs must harness the talents of all members of the healthcare team.”
“Infection preventionists and healthcare epidemiologists play a pivotal role in this approach by assisting with prompt detection of MDROs and promoting compliance with standard and transmission-based precautions,” says Julia Moody, MS, SM(ASCP), of HCA, Inc. “Infection preventionists and healthcare epidemiologists also facilitate use of other infection prevention strategies such as care bundle practices aimed at preventing bloodstream, urinary, and respiratory tract infections; hand hygiene; and education on prevention for staff, patients, and visitors. Effective prevention strategies minimize HAIs, decrease the use of additional antibiotics, and reduce MDROs.”
Antimicrobial stewardship should be considered part of a multi-faceted approach necessary to prevent, detect and control the emergence of antimicrobial-resistant organisms. Other necessary components include infection prevention best practices relating to hand hygiene, contact precautions and transmission-based precautions.
"Assiduous infection control is the most effective important component of decreasing resistant infections," says Lynfield. "There are numerous important ways that we are learning how to have an impact and many do include routine infection control measures and bundles. Infection preventionists and hospital epidemiologists in many hospitals are seeing this impact, and ensuring that infection prevention is part of an overall strategy to combat antibiotic resistance. It's important for infection preventionists and hospital epidemiologists to have an understanding of what the issues and challenges are in the different units of their hospital and to be mindful of implementing evidence-based practices, including very simple interventions such as hand hygiene and transmission-base precautions. Coupled with an antimicrobial stewardship program, these interventions can go a long way toward addressing resistant infections."
Boucher HW, Talbot GH, Bradley JS, et al. Bad bugs, no drugs: no ESKAPE! An update from the Infectious Diseases Society of America. Clin Infect Dis 2009;48:1-12.
Gilbert DN, et al. The 10×'20 Initiative: Pursuing a Global Commitment to Develop 10 New Antibacterial Drugs by 2020. Clin Infect Dis. (2010) 50(8):1081-1083.
IDSA. Statement of the Infectious Diseases Society of America (IDSA) Promoting Anti-Infective Development and Antimicrobial Stewardship through the U.S. Food and Drug Administration Prescription Drug User Fee Act (PDUFA) Reauthorization Before the House Committee on Energy and Commerce’s Subcommittee on Health. March 8, 2012.
Moody J, et al. Antimicrobial stewardship: A collaborative partnership between infection preventionists and healthcare epidemiologists. Am J Infect Control. Volume 40, Issue 2 (March 2012); and Infect Control Hosp Epidem. Volume 33, Issue 4 (April 2012).