Symposium on Infectious Diseases — February 2017
Tex Med. 2017;113(2):48-52.
By Jose M. Munita, MD; Samuel Shelburne, MD; David E. Greenberg, MD; and Cesar A. Arias, MD
The emergence and widespread dissemination of multidrug-resistant organisms is considered one of the three most important public health threats for humankind in the 21st century and jeopardizes the practice of modern medicine. Failure to tackle this problem in a comprehensive fashion could result in a dire post-antibiotic era, impairing the future development of treatments against important diseases, such as cancer, and transplant medicine, among others. Here, we provide a global perspective of the problem and describe some of the most important antibiotic-resistant organisms affecting the health of our patients. In addition, we discuss some of the ongoing efforts to deal with the antimicrobial resistance crisis.
A Major Public Health Threat
The discovery of antimicrobials is one of the most important milestones in the history of modern medicine. The antibiotic era led to a revolution in medicine, as antimicrobials became lifesaving drugs any clinician could access and provide to patients. The availability of antimicrobials became critical for the development of complex medical interventions such as cutting-edge surgical procedures, solid organ transplantation, management of patients with cancer, and advanced intensive care support for the critically ill, among others.
After billions of years, microbes have developed an immense capacity to evolve, allowing them to adapt and withstand harmful conditions. These impressive and evolving skills of natural selection have also provided them with the ability to develop different mechanisms to survive in the presence of antimicrobials. In fact, every new antimicrobial molecule that has been commercialized in clinical medicine has been followed shortly by reports of resistance. (See Figure 1.) Such bacterial genomic plasticity, coupled with the selective pressure resulting from massive antibiotic use, has led to rising rates of antimicrobial-resistant organisms.
In clinical terms, antibiotic-resistant bacteria have been categorized in three important groups: multidrug-resistant, which involves organisms that exhibit resistance to more than three families of antibiotics; extremely drug-resistant, defined as organisms in which two or fewer antimicrobials remain active in vitro; and pan-resistant, which refers to bacteria resistant to all clinically available antimicrobials (against which there are no therapeutic alternatives).1 The emergence of the latter two groups of pathogenic bacteria has become a major public health threat that virtually returns us to the pre-antibiotic era.
Indeed, in a recent survey of infectious disease specialists in the United States, 60 percent of responders indicated they had dealt with at least one pan-resistant bacterial infection within the previous year.2 As could be expected, the increasing frequency of such strains jeopardizes modern medical achievements and may influence the health of many patients around the world.
Infections caused by multidrug-resistant organisms are associated with increased mortality compared with those caused by susceptible bacteria, and they carry an important economic burden, estimated at more than $20 billion per year in the United States.3
The Centers for Disease Control and Prevention (CDC) conservatively estimates at least 23,000 people die annually in the United States as a result of an infection caused by an antibiotic-resistant organism. Moreover, according to a recent report from the United Kingdom, antibiotic resistance will cause about 300 million premature deaths by 2050, with a loss of up to $100 trillion to the global economy.4
To complicate things, there is a paucity of a robust antibiotic pipeline, with a steep decline in the number of new antibiotics approved in the United States over the last decades. The World Health Organization designated the antimicrobial resistance crisis as one of the three most important public health threats of the 21st century.5 The same organization warned failure to address this crisis would result in a catastrophic post-antibiotic era. The alarm of antimicrobial resistance has long been raised by the Infectious Diseases Society of America6 and has now been recognized as a top priority by governments and funding agencies around the world. Important efforts to increase the funding of high-quality research in this area are ongoing.
Several U.S. initiatives have been developed at the highest level of government to address the crisis. The National Strategy to Combat Antibiotic Resistance and the Interagency Task Force on Antimicrobial Resistance are high-level initiatives focused on combating the antibiotic-resistance threat. The Obama administration nearly doubled the federal funding to combat antimicrobial resistance to more than $1.2 billion in 2016. Following this move, CDC announced the release of $67 million to health departments nationwide to improve detection and identification of antibiotic-resistant bacteria, with emphasis in the local health departments of six major metropolitan areas, including Houston.
Additionally, CDC is willing to provide funding to support seven regional laboratories to deal specifically with antimicrobial-resistant bacteria, identify emerging antibiotic-resistant threats, conduct special threat assessments, and track changes in resistance. One of these laboratories is projected in Texas.
The Bacterial Threats
The list of antimicrobial-resistant human pathogens is large and continues to expand. In an attempt to prioritize efforts, CDC published a report outlining the most pressing drug-resistant organisms affecting the U.S. population. The agency categorized organisms based on the need to develop new therapies and the potential public health consequences as urgent, serious, and concerning. (See Figure 2.) The categorization helps prioritize surveillance strategies and prevention and assists in allocating funds to combat these organisms. Visit www.cdc.gov/drugresistance/biggest_threats.html for a full description of all these bacteria.
Some of the most important nosocomial organisms affecting Texas hospitals include:
The carbapenems are a group of potent, wide-spectrum antimicrobials considered to be the last resort against multidrug-resistant gram-negative organisms that cause a diverse array of serious human infections. Development of resistance against these compounds creates a major public concern. The Enterobacteriaceae family encompasses a large group of organisms that include several important human pathogens such as Escherichia coli, Klebsiella pneumoniae, and Enterobacter spp., among others.
The most frequent and worrisome mechanism of resistance to carbapenems is the acquisition of enzymes that destroy the antimicrobial molecule, rendering it ineffective. These enzymes, called carbapenemases, are encoded by genetic elements that are readily transferable among members of the Enterobacteriaceae family, and antibiotic use usually stimulates the transfer mechanism.
Many types and subtypes of such enzymes have been identified (and many others are likely to emerge), but the most widely disseminated enzyme in the United States and Texas is the KPC β-lactamase (for K. pneumoniae carbapenemase). Carbapenem-resistant Enterobacteriaceae have now been described all over the world, and their spread results in infections that are difficult, if not impossible, to treat.
In fact, recent data estimate about 50 percent of the patients who get a bloodstream infection with a carbapenem-resistant Enterobacteriaceae while admitted in a hospital die from such infection.7 Additionally, in a report in Houston, Aitken and colleagues reported on the existence of carbapenem-resistant isolates carrying an enzyme known as NDM-1 (for New Delhi metallo-beta-lactamase), first described in Sweden in a patient coming from India and rapidly spread throughout the world.8
This organism can be found in the gastrointestinal tract of healthy humans without causing major issues. However, after the use of antibiotics and alteration of the gastrointestinal microbiome (a term for the community of microbes that inhabit the gastrointestinal tract of humans), this organism seizes the opportunity and becomes an aggressive pathogen, causing significant colon inflammation that can lead to severe disease and potentially death.
C. difficile infections are most frequently seen in patients who have a history of recent antimicrobial use and/or current or previous contact with the health care environment (hospitalization, admission to long-term facilities, etc.). CDC estimates C. difficile is responsible for almost half-a-million infections per year in the United States, becoming the most common cause of health care-associated infections in the country.9 C. difficile carries economic burden calculated to up to $4.8 billion each year in excess of health care costs for acute care facilities alone.9
The number of deaths directly attributed to this infection is about 15,000 per year, and about 80 percent of these C. difficile-associated fatalities correspond to patients aged 65 years or older.9 Another challenge posed by C. difficile infection is repeat infections with the same organism (recurrence). Indeed, a CDC study found 20 percent of patients diagnosed with a health care-associated C. difficile infection experienced a recurrence of the infection after treatment,10 which exemplifies the important therapeutic conundrum that this organism represents for clinicians in Texas and nationally.
Methicillin-resistant Staphylococcus aureus
S. aureus is a major human pathogen that causes a wide range of infections (from mild skin infections to infective endocarditis), some of them life-threatening. The ability of S. aureus to adapt and develop resistance to virtually all antimicrobials used against it is concerning. In particular, the dissemination of isolates harboring resistance to most beta-lactams (known as methicillin-resistant S. aureus [MRSA]) has become a major problem in hospitals and in the community.
MRSA is a leading cause of hospital-associated infections and is the most common cause of soft-tissue infections requiring visits to emergency services in the United States.11 According to CDC estimates, each year, MRSA is responsible for more than 80,000 severe infections and causes more than 11,000 deaths in the United States. Additionally, the development of vancomycin resistance (one of the most widely used drugs to treat MRSA infections) in a community-associated genetic lineage of MRSA is particularly worrisome.12 For all these reasons, CDC catalogued MRSA as a serious threat requiring active surveillance and research efforts.
Gonorrhea is a sexually transmitted disease (STD) that can affect the urethra, cervix, pharynx, or rectum and that classically produces inflammation and discharge in the affected area. Gonorrhea is one of the most frequent STDs in the country, with CDC estimates of more than 800,000 new cases every year. Recent data suggest these numbers are increasing. When left untreated, gonorrhea can cause serious health problems that include chronic pelvic pain, life-threatening ectopic pregnancy, and even infertility. Infection (symptomatic or asymptomatic) also increases the risk of contracting and transmitting HIV.
Although historically antibiotics have successfully treated gonorrhea, N. gonorrhoeae is capable of adapting and developing resistance to nearly every drug recommended for treatment. For many years, the treatment of choice for gonorrhea was penicillin. However, an important proportion of N. gonorrhoeae isolates are now highly resistant to penicillin and other β-lactams.13 CDC estimates gonococcal organisms resistant to at least one antibiotic are responsible for around 246,000 U.S. cases of gonorrhea annually. A July 2016 publication from the Gonococcal Isolate Surveillance Project reported an increase of more than 300 percent in the number of isolates exhibiting resistance to azithromycin.14 Azithromycin is a crucial component of the currently recommended therapeutic regimen that consists of a combination of azithromycin plus ceftriaxone. Note: No treatment failures to that regimen have been reported to date; however, increasing rates of resistance to azithromycin could jeopardize the effectiveness of the current standard of care.
Vancomycin-resistant enterococci (VRE)
Enterococci are intrinsically resistant or tolerant to many antimicrobials, which explains why enterococcal infections have always been recognized as a clinical challenge. The remarkable ability of these organisms to modify their DNA has resulted in resistance to almost every antibiotic available, many times leaving clinicians with no reliable therapeutic options. VRE cause about 20,000 U.S. infections per year.3 Importantly, most of these infections occur in hospitalized patients and particularly in the severely debilitated, such as cancer patients, recipients of hematopoietic stem-cell transplants, or patients in the intensive care unit, complicating their clinical course and negatively impacting their outcomes.15
Multidrug-resistant Pseudomonas spp. and Acinetobacter spp
These organisms are gram-negative bacteria that are well-known for their ability to develop resistance to multiple antibiotics and are a common cause of health care-associated infections such as pneumonia and urinary tract and bloodstream infections. These bacteria typically produce problems in critically ill patients and cause about 1,000 deaths combined. Outcomes of severe Acinetobacter baumanii infections in subgroups of patients such as cancer and transplant patients are poor, with death rates that can reach up to 55 percent.16
Strategies to Face the Challenge
Antimicrobial resistance is a multifaceted problem, and tackling it will require the involvement of many entities, including governmental agencies, professional societies, the private sector, health care personnel, academic institutions, and the community as a whole. Different strategies to prevent the development of resistance, advancing our ability to rapidly detect multidrug-resistant organisms, controlling the spread of resistant bacteria, improving the use of currently available drugs, and promoting discovery and commercialization of novel antimicrobial compounds need to be implemented.
The "National Action Plan for Combating Antibiotic-resistant Bacteria," published in March 2015 by the Obama administration, incorporates policy recommendations of the President's Council of Advisors on Science and Technology. It's a roadmap for implementing a national effort to address the most urgent and serious multidrug-resistant threats that affect the U.S. population. The outline of this plan includes:
- Slow the emergence of resistant bacteria and prevent the spread of resistant infections. Controlling and preventing the spread of multidrug-resistant organisms is paramount to address this global crisis. Advancing our understanding of transmission dynamics and improving our infection control and antimicrobial stewardship strategies will be crucial to achieve this goal.
- Strengthen national one-health surveillance efforts to combat resistance. A successful approach to cope with antimicrobial resistance will need to consider all factors included in the development of resistant bacteria, including the understanding of the role of widespread antimicrobial use in the animal and agricultural industry and the role of the environment as a reservoir of resistant traits.
- Advance development and use of rapid, innovative diagnostic tests for identification and characterization of resistant bacteria. Advancing research and development of novel rapid diagnostics will play an important role, as these strategies will allow health professionals to improve their treatment decisions and are likely to result in better targeting of antimicrobial compounds. Rapid diagnostics can play a crucial role in the study and control of outbreak situations. Among many others, the use of genomic tools is one of the most promising techniques in the field.
- Accelerate basic and applied research and development (R&D) for new antibiotics, other therapeutics, and vaccines. As mentioned, the numbers of newly approved antibiotics has sharply decreased, as has the number of private companies investing in the field. In this area, it will be especially important to find innovative ways to fund clinically important studies, provide incentives to foster public-private partnerships, and reduce obstacles to developing novel antimicrobial molecules.
- Improve international collaboration and capacities for antibiotic-resistance prevention, surveillance, control, and antibiotic R&D. As a global problem, joining efforts with international agencies and governments is paramount to increase the efficiency of the efforts and improve our chances of success.
The immense progress of medical care achieved in the last decades is now threatened by the rise of antibiotic resistance among hospital- and community-associated pathogens. Although there is not a simple solution for this problem, we have witnessed major steps in addressing it.
Combating antibiotic resistance has now become a top public health priority in the United States and around the world and is of particular importance for Texas, which has a robust medical infrastructure dealing with millions of patients with highly complex health problems, with a high proportion of these patients requiring antibiotics during their hospital care.
Efforts by academic institutions to combat antimicrobial resistance in Texas are ongoing and include the creation by the McGovern Medical School at The University of Texas Health Science Center at Houston of a new Center for Antimicrobial Resistance and Microbial Genomics and the establishment of the Antimicrobial Resistance Cluster by the Gulf Coast Consortia (a collaboration of basic and translational scientists, researchers, clinicians, and students involving seven academic institutions in the Texas Gulf Coast area), among others. A concerted effort from scientists, physicians, government administrators, and pharmaceutical companies is necessary to win the battle against these emerging super bugs.
Jose M. Munita, MD, is associate professor of the Clinica Alemana ― Universidad del Desarrollo in Santiago, Chile, and adjunct assistant professor of The University of Texas at Houston.
Samuel Shelburne, MD, is associate professor in the departments of Infectious Diseases and Genomic Medicine at MD Anderson Cancer Center in Houston.
David E. Greenberg, MD, is an associate professor of infectious diseases and microbiology at The University of Texas Southwestern Medical Center.
Cesar A. Arias, MD, is the director of The University of Texas Center for Antimicrobial Resistance and Microbial Genomics at the McGovern Medical School at The University of Texas Health Science Center at Houston.
- Magiorakos AP, Srinivasan A, Carey RB, et al. Multidrug-resistant, extensively drug-resistant and pandrug-resistant bacteria: an international expert proposal for interim standard definitions for acquired resistance. Clin Microbiol Infect. 2012;18(3):268–281.
- Hersh AL, Newland JG, Beekmann SE, Polgreen PM, Gilbert DN. Unmet medical need in infectious diseases. Clin Infect Dis. 2012;54(11):1677–1678.
- Centers for Disease Control and Prevention. Antibiotic resistance threats in the United States, 2013. http://www.cdc.gov/drugresistance/threat-report-2013/index.html. Accessed August 25, 2016.
- O'Neill J. Antimicrobial Resistance: Tackling a Crisis for the Health and Wealth of Nations. Review on antimicrobial resistance commissioned by the United Kingdom prime minister. December 2014.
- World Health Organization. Antimicrobial resistance: global report on surveillance 2014. http://www.who.int/drugresistance/documents/surveillancereport/en/.
- Boucher HW, Talbot GH, Benjamin DK Jr, et al. 10 x '20 Progress — development of new drugs active against gram-negative bacilli: an update from the Infectious Diseases Society of America. Clin Infect Dis. 2013;56(12):1685–1694.
- van Duin D, Kaye KS, Neuner EA, Bonomo RA. Carbapenem-resistant Enterobacteriaceae: a review of treatment and outcomes. Diagn Microbiol Infect Dis. 2013;75(2):115–120.
- Aitken SL, Tarrand JJ, Deshpande LM, 35 al. High rates of nonsusceptibility to ceftazidime-avibactam and identification of New Delhi metallo-β-lactamase production in Enterobacteriaceae bloodstream infections at a major cancer center. Clin Infect Dis. 2016;63(7):954–958.
- Centers for Disease Control and Prevention. Nearly half a million Americans suffered from Clostridium difficile infections in a single year. Press release. February 25, 2015. http://www.cdc.gov/media/releases/2015/p0225-clostridium-difficile.html.
- Lessa FC, Winston LG, McDonald LC; Emerging Infections Program C. difficile Surveillance Team. Burden of Clostridium difficile infection in the United States. N Engl J Med. 2015;372(24):2369–2370.
- Talan DA, Krishnadasan A, Gorwitz RJ, et al; EMERGEncy ID Net Study Group. Comparison of Staphylococcus aureus from skin and soft-tissue infections in US emergency department patients, 2004 and 2008. Clin Infect Dis. 2011;53(2):144–149.
- Rossi F, Diaz L, Wollam A, et al. Transferable vancomycin resistance in a community-associated MRSA lineage. N Engl J Med. 2014;370(16):1524–1531.
- Unemo M, Shafer WM. Antimicrobial resistance in Neisseria gonorrhoeae in the 21st century: past, evolution, and future. Clin Microbiol Rev. 2014;27(3):587–613.
- Kirkcaldy RD, Harvey A, Papp JR, et al. Neisseria gonorrhoeae antimicrobial susceptibility surveillance ― The Gonococcal Isolate Surveillance Project, 27 Sites, United States, 2014. MMWR Surveill Summ. 2016;65(7):1–19.
- Miller WR, Murray BE, Rice LB, Arias CA. Vancomycin-resistant Enterococci: therapeutic challenges in the 21st century. Infect Dis Clin North Am. 2016;30(2):415–439.
- Perez F, Adachi J, Bonomo RA. Antibiotic-resistant gram-negative bacterial infections in patients with cancer. Clin Infect Dis. 2014;59 Suppl 5:S335–S339.