Antimicrobial resistance (AMR) and Antibacterial Resistance (ABR)

Antimicrobial resistance (AMR) is a global health and development threat that occurs when microbes (such as bacteria, viruses, fungi and parasites) evolve mechanisms that protect them from the effects of antimicrobials (drugs used to treat infections) . That means the germs are not killed and continue to grow, making infections harder to treat and increasing the risk of disease spread, severe illness and death .

Antibiotics are a type of antimicrobials that are used to treat bacterial infections. Antibacterial resistance (ABR) is a subset of AMR that refers to the resistance of bacteria to antibiotics . ABR is one of the most serious forms of AMR, as bacteria cause many common and life-threatening infections in humans and animals. ABR can also lead to the emergence and spread of multi-drug resistant (MDR) bacteria, also known as "superbugs", that are resistant to different types of antibiotics with different structures and modes of action .

AMR and ABR are driven by the misuse and overuse of antimicrobials in humans, animals and plants, as well as by the lack of access to quality antimicrobials, clean water and sanitation, and infection prevention and control measures . AMR and ABR pose a serious challenge to modern medicine, as they compromise the effectiveness of antimicrobials that are essential for treating infections, including during major surgery, cancer chemotherapy, organ transplantation and chronic diseases .

The World Health Organization (WHO) has declared that AMR is one of the top 10 global public health threats facing humanity . According to the WHO, at least 700 000 people die each year due to drug-resistant diseases, including 230 000 people who die from multidrug-resistant tuberculosis. More and more common diseases such as pneumonia, gonorrhoea, and salmonellosis are becoming harder to treat as the antibiotics used to treat them become less effective. Without urgent action, AMR could cause 10 million deaths each year by 2050 and damage the economy as much as the 2008-2009 global financial crisis .

In this article, we will explore the four mechanisms of AMR development, the difference between resistance to a particular class vs multi-drug resistance (MDR), the further classification of MDR into extensively drug-resistant (XDR) and pan drug-resistant (PDR), and the lists of priority pathogens issued by the WHO and the US Center for Disease Control and Prevention (CDC) to guide research, discovery and development of new antimicrobials. We will also discuss the possible solutions and actions that can be taken to prevent and control AMR and ABR at different levels.

AMR is the ability of microbes to resist the effects of antimicrobial drugs that are intended to kill or inhibit them. AMR can develop through four main mechanisms:

• Modifying or inactivating the drug: Some microbes can produce enzymes that break down or modify the structure of the drug, rendering it ineffective. For example, some bacteria can produce beta-lactamases that cleave the beta-lactam ring of penicillins and cephalosporins, making them resistant to these antibiotics.
• Reducing the absorption or affinity to the drug: Some microbes can alter their cell wall or membrane structure to prevent the drug from entering or binding to their target site. For example, some bacteria can modify their porins (channels that allow molecules to cross the cell membrane) to reduce the uptake of carbapenems, a class of antibiotics that target the bacterial cell wall synthesis.
• Increasing the efflux of the drug: Some microbes can pump out the drug from their cells using efflux pumps, which are transport proteins that expel various substances across the cell membrane. For example, some bacteria can overexpress efflux pumps that remove tetracyclines, a class of antibiotics that target the bacterial protein synthesis.
• Modifying the cellular components that are the target site of the drug: Some microbes can change their genetic or metabolic pathways to avoid or overcome the interference of the drug. For example, some bacteria can mutate their ribosomal RNA (rRNA) to reduce the binding of macrolides, a class of antibiotics that target the bacterial protein synthesis.

These mechanisms can be acquired by microbes either through spontaneous mutations in their own DNA or through horizontal gene transfer (HGT), which is the exchange of genetic material between different microbes. HGT can occur through three main ways: transformation (uptake of free DNA from the environment), transduction (transfer of DNA by viruses), and conjugation (transfer of DNA by direct contact between cells). HGT can facilitate the spread of AMR genes among different species and genera of microbes, creating a reservoir of resistance genes in the microbial population.

Antimicrobial resistance (AMR) can be classified into two types based on the spectrum of antimicrobials that the microbe is resistant to: resistance to a particular class and multi-drug resistance (MDR).

Resistance to a particular class means that the microbe is resistant to one type of antimicrobials that have similar structure and mechanism of action. For example, if a bacterium is resistant to penicillin and its derivatives, it is called "penicillin-resistant bacteria". This type of resistance is usually caused by a single mechanism, such as the production of an enzyme that inactivates the drug or the alteration of the target site of the drug.

Multi-drug resistance (MDR) means that the microbe is resistant to different types of antimicrobials that have different structures and modes of action. For example, if a bacterium is resistant to penicillin, cephalosporins, quinolones and aminoglycosides, it is called "multi-drug resistant bacteria". This type of resistance is usually caused by multiple mechanisms, such as the acquisition of genes that encode for different resistance factors or the activation of efflux pumps that expel the drugs out of the cell.

MDR pathogens are also known as "superbugs" because they pose a serious threat to human health and are difficult to treat. According to the World Health Organization (WHO), MDR bacteria are responsible for an estimated 700,000 deaths per year worldwide. Some examples of MDR bacteria are methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus faecium (VRE), carbapenem-resistant Enterobacteriaceae (CRE) and extended-spectrum beta-lactamase (ESBL) producing bacteria.

MDR can be further classified into extensively drug-resistant (XDR) and pan drug-resistant (PDR). XDR organisms are resistant to all available antimicrobials except one or two classes. PDR organisms are resistant to all available antimicrobials. These organisms are extremely rare but pose a serious challenge to public health. Some examples of XDR and PDR bacteria are XDR tuberculosis, XDR gonorrhea and PDR Acinetobacter baumannii.

The development and spread of AMR, especially MDR, is influenced by many factors, such as the misuse and overuse of antimicrobials in human and animal health, the lack of infection prevention and control measures in health care settings, the poor sanitation and hygiene practices in the community, the inadequate surveillance and monitoring systems for AMR, and the insufficient research and development for new antimicrobials.

Therefore, it is important to implement a comprehensive and coordinated approach to combat AMR at local, national and global levels. This includes promoting rational use of antimicrobials, strengthening infection prevention and control measures, improving surveillance and monitoring systems for AMR, enhancing public awareness and education on AMR, fostering innovation and research for new antimicrobials, diagnostics and vaccines, and strengthening international collaboration and partnership for AMR.

One of the most alarming consequences of AMR is the emergence of multi-drug resistant (MDR) pathogens, which are able to resist the action of different types of antimicrobials having different structures and modes of action. MDR pathogens pose a serious threat to human health, as they can cause infections that are difficult or impossible to treat with the available drugs. MDR pathogens are often referred to as "SUPER BUGS", as they can survive and spread in various environments and hosts.

Some examples of MDR pathogens are:

• Carbapenem-resistant Enterobacteriaceae (CRE): These are bacteria that belong to the family Enterobacteriaceae, such as Escherichia coli and Klebsiella pneumoniae, that have acquired resistance to carbapenems, a class of broad-spectrum antibiotics that are usually reserved for severe infections. CRE can cause bloodstream infections, urinary tract infections, pneumonia, and wound infections, and have a high mortality rate.
• Methicillin-resistant Staphylococcus aureus (MRSA): This is a strain of Staphylococcus aureus that has developed resistance to methicillin and other beta-lactam antibiotics, which are commonly used to treat staph infections. MRSA can cause skin and soft tissue infections, bloodstream infections, pneumonia, and surgical site infections, and can spread easily in healthcare settings and in the community.
• Vancomycin-resistant Enterococcus (VRE): This is a type of Enterococcus that has become resistant to vancomycin, an antibiotic that is often used as a last resort for treating serious infections caused by Gram-positive bacteria. VRE can cause bloodstream infections, urinary tract infections, endocarditis, and surgical site infections, and can colonize the intestines and skin of patients and healthcare workers.
• Drug-resistant Candida auris: This is a fungus that can cause invasive candidiasis, a serious infection that affects the bloodstream, heart, brain, eyes, bones, or other parts of the body. Candida auris can resist multiple antifungal drugs and can persist on surfaces and equipment in healthcare facilities. It can also spread from person to person or through contact with contaminated objects.

The development of MDR pathogens is driven by several factors, such as the overuse and misuse of antimicrobials in human and animal health, the lack of new antimicrobials in the pipeline, the poor infection prevention and control practices in healthcare settings and in the community, and the global movement of people, animals, and goods. To combat MDR pathogens, a coordinated and multifaceted approach is needed that involves improving surveillance and monitoring of AMR trends, promoting rational use of antimicrobials and adherence to treatment guidelines, enhancing infection prevention and control measures and hygiene practices, stimulating research and innovation for new antimicrobials and alternative therapies, and raising awareness and education among health professionals and the public.

As we have seen, multi-drug resistance (MDR) refers to the ability of microbes to resist the effects of different types of antimicrobials that have different structures and modes of action. However, not all MDR microbes are equally resistant. Some may still be susceptible to a few antimicrobials, while others may be resistant to all available antimicrobials. To capture this variation, MDR microbes are further classified into two categories: extensively drug-resistant (XDR) and pan drug-resistant (PDR).

XDR microbes are those that are resistant to all but one or two classes of antimicrobials. This means that there are very limited options for treating infections caused by these microbes. For example, XDR tuberculosis is a form of tuberculosis that is resistant to at least four of the six classes of drugs used to treat tuberculosis. Similarly, XDR gonorrhea is a form of gonorrhea that is resistant to all but one or two classes of antibiotics used to treat gonorrhea.

PDR microbes are those that are resistant to all available classes of antimicrobials. This means that there are no effective treatments for infections caused by these microbes. For example, PDR Acinetobacter baumannii is a type of bacteria that causes pneumonia and bloodstream infections in hospitalized patients and is resistant to all known antibiotics. Similarly, PDR Klebsiella pneumoniae is a type of bacteria that causes urinary tract infections and sepsis and is resistant to all known antibiotics.

The emergence and spread of XDR and PDR microbes pose a serious threat to public health and require urgent action to prevent and control. According to the World Health Organization (WHO), XDR and PDR microbes are among the most dangerous pathogens in the world and have the potential to cause untreatable infections and high mortality rates. The WHO has called for more research and development of new antimicrobials, diagnostics, vaccines, and other interventions to combat these superbugs.

Antimicrobial resistance (AMR) is a global health and development threat that requires urgent multisectoral action in order to achieve the Sustainable Development Goals (SDGs). The World Health Organization (WHO) has declared that AMR is one of the top 10 global public health threats facing humanity .

AMR threatens the effective prevention and treatment of an ever-increasing range of infections caused by bacteria, viruses, fungi and parasites . As a result of drug resistance, antimicrobial medicines become ineffective and infections become increasingly difficult or impossible to treat. This leads to increased morbidity, mortality, health-care costs and economic losses.

Without effective antimicrobials, the success of modern medicine in treating infections, including during major surgery and cancer chemotherapy, would be at increased risk. AMR also undermines the achievement of universal health coverage and the health-related SDGs.

The main drivers of AMR are the misuse and overuse of antimicrobials in humans, animals and plants, as well as the lack of access to quality antimicrobials, clean water and sanitation, and infection prevention and control measures. The emergence and spread of drug-resistant pathogens are facilitated by globalization, trade, travel and environmental changes.

The WHO has been leading the global response to AMR by developing global strategies, guidelines and tools, supporting countries to implement national action plans, monitoring the trends and impacts of AMR, promoting research and innovation, and fostering multisectoral collaboration among various stakeholders.

The WHO has also launched several initiatives to raise awareness and mobilize action on AMR, such as the World Antimicrobial Awareness Week (WAAW), the Global Antimicrobial Resistance Surveillance System (GLASS), the Antimicrobial Resistance Multi-Partner Trust Fund (AMR MPTF), and the One Health Global Leaders Group on Antimicrobial Resistance.

AMR is a complex and multifaceted challenge that requires a coordinated and comprehensive approach across all sectors and levels of society. The WHO calls for sustained political commitment, investment and action to combat AMR and protect human health and well-being.

The World Health Organization (WHO) has labeled AMR as one of the top 10 global public health threats. In 2017, the WHO released a list of pathogens in a report named “Global priority list of antibiotic-resistant bacteria to guide research, discovery, and development of new antibiotics”. The list was drawn up to guide and promote R&D of new antibiotics, as part of WHO’s efforts to address growing global resistance to antimicrobial medicines.

The WHO list is divided into three categories according to the urgency of need for new antibiotics: critical, high and medium priority .

• Priority 1: Critical

  It includes MDR bacteria that are mainly associated with hospital-acquired infections. It includes:

  • Carbapenem-resistant Acinetobacter baumannii (CRAB)
  • Carbapenem-resistant Pseudomonas aeruginosa (CRPA)
  • Carbapenem-resistant, Extended spectrum β-lactamase (ESBL) producing (3rd generation cephalosporin-resistant) Enterobacteriaceae (Among the Enterobacteriaceae, E. coli, Klebsiella pneumoniae, Proteus spp., Serratia spp., Providentia spp., Morganella spp., and Enterobacter spp. are of major concern)

• Priority 2: High

  It includes bacteria that cause common infections such as bloodstream infections, surgical site infections, and gastrointestinal infections. It includes:

  • Vancomycin-resistant Enterococcus faecium
  • Methicillin-resistant, vancomycin-intermediate, and resistant Staphylococcus aureus
  • Clarithromycin-resistant Helicobacter pylori
  • Fluoroquinolone-resistant Campylobacter spp.
  • Fluoroquinolone-resistant Salmonella
  • 3rd generation cephalosporin-resistant, fluoroquinolone-resistant Neisseria gonorrhoeae

• Priority 3: Medium

  It includes bacteria that cause less severe but still important infections such as respiratory tract infections and skin infections. It includes:

  • Penicillin-non-susceptible Streptococcus pneumoniae
  • Ampicillin-resistant Haemophilus influenzae
  • Fluoroquinolone-resistant Shigella spp.

The list highlights in particular the threat of gram-negative bacteria that are resistant to multiple antibiotics. These bacteria have built-in abilities to find new ways to resist treatment and can pass along genetic material that allows other bacteria to become drug-resistant as well. The list also reflects the need for new antibiotics for tuberculosis, which is not included in the list because it is already a globally established priority for which innovative new treatments are urgently needed.

The list is intended to spur governments to put in place policies that incentivize basic science and advanced R&D by both publicly funded agencies and the private sector investing in new antibiotic discovery. The list is also meant to inform the public, health professionals, policy-makers and stakeholders about the urgent need for new antibiotics for these priority pathogens.

In 2019, the US CDC released a list of resistant bacteria and fungi in the CDC’s 2019 AR Threat Report. This list includes bacteria listed in the WHO’s 2017 list but contains additional pathogens of concern in the US. The CDC has categorized the resistant pathogens into four threat levels: urgent, serious, concerning, and watch.

Urgent Threats

This level includes five pathogens that require urgent and aggressive actions to prevent and control their spread. They are:

• Carbapenem-resistant Acinetobacter (CRAB): These bacteria can cause pneumonia, bloodstream infections, wound infections, and urinary tract infections. They are resistant to most antibiotics, including carbapenems, which are considered last-resort drugs. CRAB infections are mainly associated with healthcare settings and affect people with weakened immune systems or chronic diseases. CRAB infections are estimated to cause more than 8,500 infections and 700 deaths in the US each year.

• Drug-resistant Candida auris (C. auris): This is a fungus that can cause serious and sometimes fatal infections in the bloodstream, brain, heart, and other organs. It is resistant to multiple antifungal drugs and can spread easily in healthcare settings. It can also persist on surfaces and equipment for a long time. C. auris infections are estimated to cause more than 1,600 cases and 300 deaths in the US each year.

• Clostridioides difficile (C. difficile): This is a bacterium that can cause severe diarrhea, colitis, and death. It is not resistant to antibiotics but can overgrow in the gut when antibiotics disrupt the normal flora. It can also produce spores that can contaminate the environment and infect other people. C. difficile infections are estimated to cause more than 223,000 cases and 12,800 deaths in the US each year.

• Carbapenem-resistant Enterobacteriaceae (CRE): These are a group of bacteria that belong to the Enterobacteriaceae family, such as E. coli and Klebsiella. They can cause various infections, such as urinary tract infections, bloodstream infections, wound infections, and meningitis. They are resistant to most antibiotics, including carbapenems, which are considered last-resort drugs. CRE infections are mainly associated with healthcare settings and affect people with weakened immune systems or chronic diseases. CRE infections are estimated to cause more than 13,100 cases and 1,100 deaths in the US each year.

• Drug-resistant Neisseria gonorrhoeae (N. gonorrhoeae): This is a bacterium that causes gonorrhea, a sexually transmitted infection that can affect the genitals, rectum, throat, and eyes. It can also cause complications such as pelvic inflammatory disease, infertility, ectopic pregnancy, and increased risk of HIV infection. N. gonorrhoeae is resistant to most antibiotics used to treat it and only one class of antibiotics remains effective. N. gonorrhoeae infections are estimated to cause more than 550,000 cases in the US each year.

Serious Threats

This level includes 11 pathogens that require prompt and sustained actions to prevent and control their spread. They are:

• Drug-resistant Campylobacter: This is a bacterium that causes campylobacteriosis, a foodborne illness that can cause diarrhea, fever, abdominal cramps, and sometimes complications such as Guillain-Barré syndrome and reactive arthritis. It is resistant to some antibiotics used to treat it, such as fluoroquinolones and macrolides. Drug-resistant Campylobacter infections are estimated to cause more than 475,000 cases in the US each year.

• Drug-resistant Candida: These are fungi that cause candidiasis, a common infection that can affect the mouth, throat, vagina, skin, bloodstream, and other organs. Some Candida species are resistant to some antifungal drugs used to treat them, such as azoles and echinocandins. Drug-resistant Candida infections are estimated to cause more than 25,000 cases in the US each year.

• Extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBL-E): These are a group of bacteria that belong to the Enterobacteriaceae family, such as E. coli and Klebsiella. They can produce enzymes called ESBLs that can break down some antibiotics used to treat them, such as penicillins and cephalosporins. ESBL-E can cause various infections, such as urinary tract infections, bloodstream infections, wound infections, and meningitis. ESBL-E infections are mainly associated with healthcare settings and affect people with weakened immune systems or chronic diseases. ESBL-E infections are estimated to cause more than 197, 000 cases and 9, 100 deaths in the US each year.

• Vancomycin-resistant Enterococci (VRE): These are bacteria that belong to the Enterococcus genus, such as E. faecalis and E. faecium. They can cause various infections, such as urinary tract infections, bloodstream infections, wound infections, and endocarditis. They are resistant to vancomycin, which is one of the main antibiotics used to treat them. VRE infections are mainly associated with healthcare settings and affect people with weakened immune systems or chronic diseases. VRE infections are estimated to cause more than 54, 500 cases and 5, 400 deaths in the US each year.

• Multidrug-resistant Pseudomonas aeruginosa (MDR-PA): This is a bacterium that can cause various infections, such as pneumonia, bloodstream infections, wound infections, and urinary tract infections. It is resistant to multiple antibiotics used to treat it, such as carbapenems, aminoglycosides, and fluoroquinolones. MDR-PA infections are mainly associated with healthcare settings and affect people with weakened immune systems or chronic diseases. MDR-PA infections are estimated to cause more than 32, 600 cases and 2, 700 deaths in the US each year.

• Drug-resistant non-typhoidal Salmonella (NTS): These are bacteria that belong to the Salmonella genus, such as S. Typhimurium and S. Enteritidis. They cause salmonellosis, a foodborne illness that can cause diarrhea, fever, abdominal cramps, and sometimes complications such as septicemia, meningitis, and osteomyelitis. Some NTS strains are resistant to some antibiotics used to treat them, such as ampicillin, chloramphenicol, trimethoprim-sulfamethoxazole, and ciprofloxacin. Drug-resistant NTS infections are estimated to cause more than 100, 000 cases in the US each year.

• Drug-resistant Salmonella serotype Typhi (S. Typhi): This is a bacterium that causes typhoid fever, a systemic infection that can cause fever, headache, abdominal pain, and sometimes complications such as intestinal perforation, hemorrhage, and death. It is transmitted by contaminated food or water in areas with poor sanitation. Some S. Typhi strains are resistant to multiple antibiotics used to treat them, such as ampicillin, chloramphenicol, trimethoprim-sulfamethoxazole, and fluoroquinolones. Drug-resistant S. Typhi infections are estimated to cause more than 5, 700 cases in the US each year.

• Drug-resistant Shigella: These are bacteria that belong to the Shigella genus, such as S.sonneiand S.flexneri.They cause shigellosis, a foodborne illness that can cause diarrhea, fever,abdominal cramps, and sometimes complications such as dysentery, hemolytic uremic syndrome, and reactive arthritis.Some Shigella strains are resistant to some antibiotics used to treat them, such as ampicillin, trimethoprim-sulfamethoxazole, and ciprofloxacin.Drug-resistant Shigella infections are estimated to cause more than 27, 000 casesin the US each year.

• Methicillin-resistant Staphylococcus aureus (MRSA): This is a bacterium that belongs to the Staphylococcus genus, such as http://s.aureus.it/ can cause various skin and soft tissue infections, such as boils, abscesses, cellulitis, and http://impetigo.it/ can also cause invasive infections, such as pneumonia, bloodstream infections, endocarditis, osteomyelitis, and http://sepsis.it/ is resistant to methicillin and other beta-lactam antibiotics used to treat it.MRSA infections can occur both in healthcare settings and in community settings among healthy people.MRSA infections are estimated to cause more than 323, 700 cases and 10,600 deaths in the US each year.Drug-resistant Streptococcus pneumoniae (S.pneumoniae): This is a bacterium that belongs to the Streptococcus genus, such as S.pneumoniae .It can cause various respiratory tract infections, such as otitis media, sinusitis.

Antimicrobial resistance (AMR) and antibacterial resistance (ABR) are serious global threats that affect human health, animal health, food security and the environment. They are driven by multiple factors, such as misuse and overuse of antimicrobials, lack of infection prevention and control measures, poor sanitation and hygiene, inadequate surveillance and diagnostics, and insufficient research and development of new drugs. AMR and ABR can result in increased morbidity, mortality, healthcare costs and economic losses. They can also compromise the effectiveness of existing treatments and jeopardize the achievements of modern medicine.

To tackle this complex and multifaceted challenge, a coordinated and collaborative approach is needed among all stakeholders, including governments, health professionals, researchers, industry, civil society and the public. A One Health perspective that recognizes the interconnection between humans, animals and the environment is essential to address the root causes and drivers of AMR and ABR. The implementation of national action plans based on the WHO Global Action Plan on AMR is a key step to align policies and strategies across different sectors and levels. Moreover, the promotion of awareness, education, stewardship and innovation is crucial to foster responsible use of antimicrobials, prevent infections, improve diagnostics and develop new drugs.

AMR and ABR are not inevitable phenomena that we have to accept. They are preventable and manageable problems that we can solve with collective action and commitment. By working together, we can preserve the power of antimicrobials for current and future generations.

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