The Growing Threat of Antibiotic-Resistant Illnesses

SINCE PENICILLIN WAS first used in humans in 1942, doctors have been treating patients who suffer from bacterial infections with antibiotic drugs, the most commonly prescribed drugs used in human medicine, with exceptional success. Antibiotics have greatly reduced illness, disability, morbidity and mortality from infectious diseases in millions of people in the United States and globally. But, after almost 80 years of long-term widespread use and overuse, overprescription by physicians of antibiotics for nonbacterial infections, and either misuse or abuse of antibiotic prescriptions by patients, the resulting phenomenon is antimicrobial resistance (AMR). Indeed, the global threat of antibiotic-resistant illnesses is so prevalent that the World Health Organization (WHO) classified it as a “serious threat [that] is no longer a prediction for the future, it is happening right now in every region of the world and has the potential to affect anyone, of any age, in any country.”¹

AMR versus Antibiotic Resistance

According to WHO, AMR occurs when microorganisms such as bacteria, viruses, fungi and parasites change in ways that render the medications used to cure the infections they cause ineffective. When microorganisms become resistant to most antimicrobials, they are often referred to as “superbugs.” AMR is the broader term for resistance in different types of microorganisms and encompasses resistance to antibacterial, antiviral, antiparasitic and antifungal drugs. Antibiotic resistance, specifically, occurs when bacteria change in response to the use of antibiotics used to treat bacterial infections (such as urinary tract infections, pneumonia and bloodstream infections), making them ineffective.²

How Does Antibiotic Resistance Occur?

Alexander Kallen, MD, MPH, a medical epidemiologist and outbreak response coordinator in the Division of Healthcare Quality Promotion at the Centers for Disease Control and Prevention (CDC), says antibiotic resistance can manifest in two ways: “First, in some situations, bacteria that is initially sensitive to antibiotics becomes resistant when the bacteria are exposed time and time again to the antibiotic. This is called inducible resistance and can happen through a mutation in the bacteria or when the bacteria ‘turns on’ a resistance mechanism that it already has. Second, bacteria that is already resistant to antibiotics can be transmitted from one person to another and can cause an infection. Antibiotics can also play a role here as these drugs can destroy a person’s normal sensitive bacteria, providing a niche for these resistant bacteria to exploit.”

CDC outlines two pathways in which antibiotic resistance can spread. In the first pathway, animals receive antibiotics and develop resistant bacteria in their guts. Because drug-resistant bacteria can remain on meat from animals, when it is not handled or cooked properly, the bacteria can spread to humans. Also, fertilizer or water containing animal feces and drug-resistant bacteria is used and can remain on food crops, which can then be transferred to the human gut.

In the second pathway, individuals who receive antibiotics can develop resistant bacteria in their gut, which they can then spread to the general community. Or, patients who receive care at a hospital, nursing home or other inpatient care facility can develop resistant bacteria in their gut and either a) the resistant bacteria can spread to other patients from surfaces within the healthcare facility or b) the resistant germs can spread directly to other patients or indirectly on unclean hands of healthcare providers. After the patients go home, they can spread resistant bacteria in the general community.³

WHO further explains how AMR occurs when microorganisms such as bacteria, fungi, viruses and parasites are exposed to antimicrobial drugs such as antibiotics, antifungals, antivirals, antimalarials and anthelmintics. While AMR occurs naturally over time, usually through genetic changes, exposure to drugs kills the sensitive strains and encourages proliferation of resistant ones. As previously stated, microorganisms that develop antimicrobial resistance to multiple drugs are referred to as “superbugs.” With superbugs, medicines become ineffective, and infections persist in the body, increasing the risk of spread to others.

In addition, says WHO, AMR microbes are found in people, animals, food and the environment (in water, soil and air), and they can spread between people and animals, including from food of animal origin and from person to person. Poor infection control, inadequate sanitary conditions and inappropriate food handling encourage the spread of AMR. However, says WHO, misuse and overuse of antimicrobials are accelerating the AMR process. In many places, antibiotics are overused and misused in people and animals, and they are often given without professional oversight.⁴

What Are the Most Common AMR Illnesses?

According to CDC, 18 bacteria cause severe infections in humans. These bacteria are categorized into three levels of antibiotic-resistant threats: urgent, serious and concerning.³

Urgent threat bacteria include:

• Clostridium difficile
• Carbapenem-resistant Enterobacteriaceae
• Drug-resistant Neisseria gonorrhoeae

Serious threat bacteria include:

• Multidrug-resistant Acinetobacter
• Drug-resistant Campylobacter
• Fluconazole-resistant Candida (a fungus)
• Extended spectrum β-lactamase producing Enterobacteriaceae
• Vancomycin-resistant Enterococcus
• Multidrug-resistant Pseudomonas aeruginosa
• Drug-resistant non-typhoidal Salmonella
• Drug-resistant Salmonella Typhi
• Drug-resistant Shigella
• Methicillin-resistant Staphylococcus aureus
• Drug-resistant Streptococcus pneumoniae
• Drug-resistant tuberculosis Concerning threat bacteria include:
• Vancomycin-resistant Staphylococcus aureus
• Erythromycin-resistant Group A Streptococcus
• Clindamycin-resistant Group B Streptococcus

AMR bacterial infection consequences include prolonged and/or more complicated illnesses; compromised success of organ transplants, major surgery and cancer chemotherapy; more expensive tests and/or treatments; use of stronger and/or more expensive drugs; additional doctor visits and more healthcare use (extended hospital stays); higher healthcare costs; and dramatically higher rates of infections, disabilities, morbidity and mortality.³

How Is Antibiotic Resistance Being Addressed?

Many government organizations have made tremendous headway to address the spread of resistant bacteria in the last several years.

• In November 2017, CDC kicked off U.S. Antibiotic Awareness Week and World Antibiotic Awareness Week. CDC recognizes U.S. Antibiotic Awareness Week with an updated education effort titled Be Antibiotics Aware: Smart Use, Best Care (formerly Get Smart About Antibiotics), which is an annual one-week observance to raise awareness of the threat of antibiotic resistance and the importance of appropriate antibiotic prescribing and use. 5,6 “Prescribing the right antibiotic at the right time, in the right dose and for the right duration helps fight antibiotic resistance, protects patients from unnecessary side effects and helps ensure these lifesaving medicines will be available for future generations,” says CDC.⁷
• In 2016, CDC implemented the Antibiotic Resistance (AR) Solutions Initiative that supports national infrastructure to detect, respond, contain and prevent resistant infections across healthcare settings, food and communities. The AR Solutions Initiative’s goals are to improve antibiotic use through antibiotic stewardship, sepsis recognition and prevention through: 1) setting national goals to improve antibiotic use (cut inappropriate prescribing practices by 50 percent in doctor offices and 20 percent in hospitals); 2) implementing effective stewardship programs using CDC’s Core Elements in doctor offices, hospitals and nursing homes, and integrated with sepsis early recognition programs; 3) supporting collaboration to develop and evaluate stewardship activities; 4) providing data about antibiotic use and trends to better understand prescribing practices; 5) expanding state healthcare-associated infections and AR prevention programs to help implement best practices; and 6) supporting early recognition of sepsis.⁸

Under the AR Solutions Initiative, CDC built the AR Laboratory Network that can identify resistant bacteria quicker and stop its spread with interventions supported by public health. The initiative also puts state and local AR laboratory and epidemiological expertise in every state and makes investments in public health innovation to fight AR across healthcare settings, food and communities.⁹ According to Dr. Kallen, “Many states now have the capacity to react when just a single instance of a bacteria with high levels of resistance is identified from a clinical culture. Reductions in the proportion of infections caused by some resistant bacteria have already been noted. In a recent publication, the CDC showed that the proportion of a type of healthcare infection caused by a highly resistant bacteria called carbapenem-resistant Enterobacteriaceae, or CRE, fell from 10.6 percent to 3.1 percent between 2006 and 2015.”

Also under the AR Solutions Initiative is the AR Investment Map that shows the activities to meet national goals to prevent drug-resistant infections. The 2017 map features more than 170 state-reported successes such as rapidly identifying and containing rare and concerning resistant germs to protect communities, with each state reporting multiple successes.¹⁰

• In June 2015, CDC and the U.S. Food and Drug Administration (FDA) created the Antibiotic Resistance Isolate Bank that provides information on resistance to support innovation in diagnostics and drug development. Under this program, CDC provides isolates (bacteria isolated from a specimen such as blood or food) to approved institutions. The AR Isolate Bank helps to 1) strengthen diagnostics by validating lab tests; 2) inform research and development to develop drugs such as antibiotics and antifungals; diagnostic devices, tests or assays; and satisfy a request or support an application to FDA; 3) perform testing to ensure drug effectiveness; 4) study biology and pathogenic mechanisms; and 5) detect new and unusual public health resistance threats.

The AR Isolate Bank is unique because CDC has one of the largest collections of isolates gathered from national reference labs and tracking activities taken from specimens in healthcare, food and the community. In the bank, samples are assembled based on public health threats, isolates are delivered in panels rather than piecemealed, researchers can quickly and easily obtain the specific samples they need, obstacles that might keep companies or researchers from engaging in finding resistance solutions are reduced, samples are accompanied by publicly available data to improve efficiencies, and a convenient ordering system increases efficiency.¹¹

• Under the National Action Plan for Combating AntibioticResistant Bacteria (CARB), a five-year plan created in March 2015, the United States is working domestically and internationally to prevent, detect and control illness and death related to infections caused by resistant bacteria by implementing measures to mitigate the emergence and spread of antibiotic resistance and ensuring the continued availability of therapeutics for the treatment of bacterial infections. The goals of CARB include 1) slowing the emergence of resistant bacteria and preventing the spread of resistant infections; 2) strengthening national One-Health Surveillance efforts to combat resistance; 3) advancing development and use of rapid and innovative diagnostic tests for identification and characterization of resistant bacteria; 4) accelerating basic and applied research and development for new antibiotics, other therapeutics and vaccines; and 5) improving international collaboration and capacities for antibiotic-resistance prevention, surveillance and control and antibiotic research and development.

CARB will also result in improved antibiotic stewardship in healthcare settings, prevention of the spread of drug-resistant threats, elimination of the use of medically important antibiotics for growth promotion in food animals, and expanded surveillance for drug-resistant bacteria in humans and animals. Other significant outcomes include creation of a regional public health laboratory network, establishment of a specimen repository and sequence database that can be accessed by industrial and academic researchers, development of new diagnostic tests through a national challenge, and development of two or more antibiotic drug candidates or nontraditional therapeutics for treatment of human disease.¹²

• Established in 1996, the National Antimicrobial Resistance Monitoring System for Enteric Bacteria (NARMS) is a collaboration among CDC, FDA and the U.S. Department of Agriculture (USDA), as well as state and local public health departments. This national public health surveillance system tracks changes in the antimicrobial susceptibility of certain enteric (intestinal) bacteria found in ill people (CDC), retail meats (FDA) and food animals (USDA) in the United States. NARMS helps protect public health by providing information about emerging bacterial resistance, the ways in which resistance is spread and how resistant infections differ from susceptible infections.¹³
• In cooperation with other government agencies, FDA has launched several initiatives to address antibiotic resistance. Initiatives include drug-labeling regulations that emphasize the prudent use of antibiotics and encourage healthcare professionals to prescribe antibiotics only when clinically necessary and to counsel patients about the proper use of such drugs and the importance of taking them as directed. FDA is also encouraging the development of new drugs, vaccines and improved tests for infectious diseases.¹⁴
• FDA participates on the Interagency Task Force on Antimicrobial Resistance created in 1999. Co-chaired by CDC and the National Institutes of Health, it includes nine participating agencies and includes 11 goals divided into four focus areas. Focus Area I: Surveillance aims to improve the detection, monitoring and characterization of drug-resistant infections in humans and animals. Focus Area II: Prevention and Control aims to develop, implement and evaluate strategies to prevent the emergence, transmission and persistence of drug-resistant microorganisms. Focus Area III: Research aims to encourage, conduct and support basic and translational research to enhance the understanding of factors leading to the development of AMR microorganisms, their transmission in various settings and optimal modes of prevention, diagnosis and therapy. Focus Area IV: Product Development aims to encourage the development of new antimicrobial products to improve the capacity to diagnose, prevent and treat infections, including infections caused by resistant microorganisms.¹⁵
• FDA’s Limited Population Pathway for Antibacterial and Antifungal Drugs: Guidance for Industry (LPAD Pathway) issued draft guidance “describing criteria, processes and other general considerations for demonstrating the safety and effectiveness of limited population antibacterial and antifungal drugs.” This guidance is intended to assist sponsors in developing certain new antibacterial and antifungal drugs for approval under the LPAD Pathway. It is also intended to assist sponsors in developing labeling, including prescribing information, patient labeling and carton/container labeling.¹⁶
• FDA issued the final guidance Antibacterial Therapies for Patients with an Unmet Medical Need for the Treatment of Serious Bacterial Diseases: Guidance for Industry in August 2017. This guidance is intended to assist sponsors in the clinical development of new antibacterial drugs. Specifically, the guidance explains FDA’s current thinking about possible streamlined development programs and clinical trial designs for antibacterial drugs to treat serious bacterial diseases in patients with an unmet medical need, including patients who have a serious bacterial disease for which effective antibacterial drugs are limited or lacking.¹⁷
• Like the CDC and FDA, WHO has been leading multiple initiatives to address AMR. In October 2015, WHO, the Food and Agriculture Organisation of the United Nations and World Organization for Animal Health implemented the Global Action Plan on Antimicrobial Resistance (GAP). GAP comprises surveillance, education, monitoring and regulating consumption and use of antimicrobials in human health, animal health and production, as well as plants and the environment. The goals of GAP are to ensure prevention and treatment of infectious diseases with safe and effective medicines. It includes five strategic objectives: 1) Improve awareness and understanding of AMR; 2) Strengthen surveillance and research; 3) Reduce the incidence of infection; 4) Optimize the use of antimicrobial medicines; and 5) Ensure sustainable investment in countering AMR.¹⁸
• In its report dated July 18, 2018, WHO says, “Countries are making significant steps in tackling antimicrobial resistance, but serious gaps remain and require urgent action.” The report charts progress in 154 out of 194 countries responding and reveals wide discrepancies. Specifically, it looks at surveillance, education, monitoring and regulating consumption and use of antimicrobials in human health, animal health and production, as well as plants and the environment, as recommended in GAP.¹⁹
• Every November since 2015, WHO supports global and national action for World Antibiotic Awareness Week with the theme “Antibiotics: Handle with Care.” The global, multi-year campaign includes an increasing volume of activities during the week of the campaign.²⁰
• In October 2015, WHO launched the Global Antimicrobial Surveillance System (GLASS) to support GAP on AMR. Early implementation of GLASS is from 2015 through 2019. Its aim is to support global surveillance and research to strengthen the evidence base on AMR and to help inform decision-making and drive national, regional and global actions. GLASS promotes and supports a standardized approach to the collection, analysis and sharing of AMR data at a global level by encouraging and facilitating the establishment of national AMR surveillance systems capable of monitoring AMR trends and producing reliable and comparable data.

The six GLASS objectives are: 1) Foster national surveillance systems and harmonized global standards; 2) Estimate the extent and burden of AMR globally by selected indicators; 3) Analyze and report global data on AMR on a regular basis; 4) Detect emerging resistance and its international spread; 5) Inform implementation of targeted prevention and control programs; and 6) Assess the impact of interventions. 21 WHO’s first release of surveillance data on AMR on Jan. 29, 2018, revealed high levels of resistance to a number of serious bacterial infections in both high- and low-income countries. Specifically, GLASS revealed widespread occurrence of antibiotic resistance among 500,000 people with suspected bacterial infections across 22 countries.²²

• In a joint initiative of WHO and the Drugs for Neglected Diseases initiative (DNDi), the Global Antibiotic Research and Development Partnership (GARDP) was created in May 2016 as an important element of WHO’s GAP on AMR, which calls for new public-private partnerships to encourage research and development of new antimicrobial agents and diagnostics. GARDP addresses global public health needs by developing and delivering new or improved antibiotic treatments, while endeavoring to ensure their sustainable access. It aims to develop and deliver new treatments for bacterial infections where drug resistance is present or emerging, or for which inadequate treatment exists. By 2023, the partnership aims to develop and deliver up to four new treatments through improving existing antibiotics and accelerating the entry of new antibiotics.²³
• The United Nations (UN) secretary-general established the Interagency Coordination Group on Antimicrobial Resistance (IACG) to improve coordination between international organizations and ensure effective global action. The IACG is co-chaired by the UN deputy secretary-general and the director general of WHO and comprises high-level representatives of relevant UN agencies, other international organizations and individual experts across different sectors.²⁴
• Originally launched in 1977, WHO’s Essential Medicines List (ELM) for 2017 provides new advice on which antibiotics to use for common infections and which to preserve for the most serious circumstances. ELM groups antibiotics into three categories — ACCESS, WATCH and RESERVE — with recommendations on when each category should be applied. ELM recommends antibiotics in the ACCESS group be available at all times as treatments for a wide range of common infections. The WATCH group includes antibiotics recommended as first- or second-choice treatments for a small number of infections. And, antibiotics in the RESERVE group are considered last-resort options and used only in the most severe circumstances when all other alternatives have failed such as for life-threatening infections due to multidrug-resistant bacteria.²⁵
• In 2017, WHO developed the Global Priority Pathogens List (Global PPL) whose major objective is to guide the prioritization of incentives and funding, help align research and development priorities with public health needs, and support global coordination in the fight against antibiotic-resistant bacteria. Global PPL of bacteria is divided into three areas (12 families of bacterial “supervillains” considered the most serious threats to human health): Priority 1: Critical includes thethree most feared resistant bacteria in the world. These bacteria thrive in hospitals and facilities and infect patients on ventilators and catheters, causing potentially deadly blood and respiratory infections. They are resistant to even the most powerful antibiotics. Priority 2: High and Priority 3: Medium include a list of the other nine high- and medium-risk resistant bacteria.²⁶

Looking Ahead

According to Dr. Kallen, CDC believes bacteria will continue to develop new ways to evade the effects of the best antibiotic drugs: “As long as we rely on these drugs to combat infections, we will need to be vigilant to the threat of antimicrobial resistance. The new investments that the CDC has made in infrastructure to detect and respond to antibiotics has made our ability to respond to new and emerging threats more nimble and more effective. With these new tools, we can slow the spread of resistant bacteria.”

Elizabeth Tayler, team lead of the National Action Plans and Monitoring Team with WHO, adds: “Addressing antimicrobial resistance properly involves strengthening systems that detect, prevent and manage infection in human health, decreasing the overuse of antibiotics in food production and reducing environmental contamination. These actions need to happen in a sustainable way, at scale. To achieve this will be quite a challenge for high-income countries, but it is particularly challenging for low-income countries. Therefore, it is unlikely that all countries will ever be able to reach the highest levels in all elements of the Global Action Plan, but we encourage all countries to focus on those areas that will havethe highest impact and are most readily achievable. It is vital that this happens over the next five years as resistance levels are rising across the world.”