Resistant organisms are microbes—bacteria, fungi, viruses, or parasites—that have evolved immunity to one or more of the drugs used to kill them. Drugs that kill microbes are called antimicrobials. Resistance threatens human health because it reduces or eliminates the efficacy of drugs used to treat infections. If organisms evolve resistance to drugs faster than new drugs can be discovered, doctors’ choices for treating infections by those organisms dwindle. This has happened for many real-world bacteria, viruses, fungi, and parasites. Resistance to a drug is more likely to evolve when the drug is widely used. Antibiotic resistance, in particular, has arisen in part because of chronic overuse of antibiotics in medical and agricultural settings. Antibiotics are often prescribed for viral, not bacterial, infections (antibiotics have no effect on viruses), and millions of pounds of antibiotics are given to livestock each year. Most experts agree that in the early twenty-first century, anti-microbial resistance has reached a crisis stage.
Resistant organisms did not arise before the mid-twentieth century because antimicrobials potent enough to force the evolution of resistance were not known. Penicillin, for example, was discovered in 1928 and was first widely used during World War II (1939–45). Penicillin-resistant Escherichia coli bacteria were first observed in 1940. Penicillin-resistant staphylococcus bacteria were reported in 1944, and, by the 1950s, a penicillin-resistant strain of Staphylococcus aureus became a worldwide problem in hospitals. By the 1960s, most staphylococci were resistant to penicillin.
Another example of resistance development is the malaria parasite and the antimalarial drug chloroquine.
Chloroquine was introduced in the 1940s. Ten years later, resistance to chloroquine evolved independently in Asia and South America but remained rare. After another twenty years, resistance appeared in East Africa and spread rapidly thereafter. Today, chloroquine-resistant malaria is found in several regions across the globe. Malaria infects 300 to 500 million people yearly, killing about 1 million, almost all in developing nations.
Since the late 1980s, pathogens resistant to more than one drug—which are even more difficult to treat than organisms with single-drug resistance—have emerged at an accelerating pace. However, development of new anti-microbials has slowed.
In any wild population of microorganisms, whether bacteria or viruses, there will be small, random, heritable differences—genetic differences—between individuals. The protein recipe for a microorganism is not rigid and exact; its many proteins can take on slightly different forms without compromising its ability to survive. When a population of microorganisms is exposed to a drug designed to destroy it, the genetic differences between individuals sometimes allow microorganisms to survive. Thus, the entire next generation of microorganisms will tend to be more resistant to that drug. If this evolutionary process of variation and selection is repeated, resistance can evolve.
In general, the more often a drug is used, the more quickly resistance may evolve. However, resistance can also evolve when insufficient quantities of a drug are used and some microorganisms survive. The fewer survivors there are, the more resistant they may be. Thus dosing to the threshold of elimination can be worse than drastically underdosing (which does not select so strongly for resistance).
Resistance may still evolve even if drugs are dosed appropriately. This has been the case with antivirals, antifungals, and antiparasitics. However, needless or inadequate use of antimicrobials encourages more rapid evolution of resistance.
WORDS TO KNOW
ANTIBACTERIAL: A substance that reduces or kill germs (bacteria and other microorganisms but not including viruses). Also often a term used to describe a drug used to treat bacterial infections.
ANTIBIOTIC: A drug, such as penicillin, used to fight infections caused by bacteria. Antibiotics act only on bacteria and are not effective against viruses.
ANTIFUNGAL: Antifungals (also called antifungal drugs) are medicines used to fight fungal infections. They are of two kinds, systemic and topical. Systemic antifungal drugs are medicines taken by mouth or by injection to treat infections caused by a fungus. Topical antifungal drugs are medicines applied to the skin to treat skin infections caused by a fungus.
ANTIMICROBIAL: A material that slows the growth of bacteria or that is able to kill bacteria. Includes antibiotics (which can be used inside the body) and disinfectants (which can only be used outside the body).
BACTERIA: Single-celled microorganisms that live in soil, water, plants, and animals that play a key role in the decay of organic matter and the cycling of nutrients. Some bacteria are agents of disease. Microscopic organisms whose activities range from the development of disease to fermentation. Bacteria range in shape from spherical to rod-shaped to spiral. Different types of bacteria cause many sexually transmitted diseases, including syphilis, gonorrhea, and chlamydia. Bacteria also cause diseases ranging from typhoid to dysentery to tetanus. Bacterium is the singular form of bacteria.
COHORT: A cohort is a group of people (or any species) sharing a common characteristic. Cohorts are identified and grouped in cohort studies to determine the frequency of diseases or the kinds of disease outcomes over time.
DRUG RESISTANCE: Drug resistance develops when an infective agent such as a bacterium, fungus or virus, develops a lack of sensitivity to a drug that would normally be able to control or even kill them. This tends to occur with over-use of anti-infectives, which selects out populations of microbes most able to resist them, while killing off those organisms that are most sensitive. The next time the anti-infective agent is used, it will be less effective, leading to the eventual development of resistance.
MICROORGANISM: Microorganisms are minute organisms. With the single yet-known exception of a bacterium that is large enough to be seen unaided, individual microorganisms are microscopic in size. To be seen, they must be magnified by an optical or electron microscope. The most common types of microorganisms are viruses, bacteria, blue-green bacteria, some algae, some fungi, yeasts, and protozoans.
PATHOGEN: A disease causing agent, such as a bacteria, virus, fungus, etc.
VIRUS: Viruses are essentially nonliving repositories of nucleic acid that require the presence of a living prokaryotic or eukaryotic cell for the replication of the nucleic acid. There are a number of different viruses that challenge the human immune system and that may produce disease in humans. In common, a virus is a small, infectious agent that consists of a core of genetic material (either deoxyribonucleic acid (DNA) or ribonucleic acid (RNA) surrounded by a shell of protein. Very simple microorganisms, viruses are much smaller than bacteria that enter and multiples within cells. Viruses often exchange or transfer their genetic material (DNA or RNA) to cells and can cause diseases such as chickenpox, hepatitis, measles, and mumps.
The features that make an organism resistant to a drug vary widely because the precise ways in which anti-microbials attack organisms vary widely. Any mutation that interferes with the harmful action of the drug on the organism will confer resistance. For example, some bacteria have become resistant to the antibiotic penicillin by evolving the ability to produce beta-lactamases, which are enzymes (a type of protein) that deactivate the anti-biotic. In other cases, microorganisms utilize several methods of antibiotic resistance: learning how to keep drugs from passing into the cell or accumulating there; altering surface molecules that antimicrobial drugs bind to; or evolving alternatives to series of chemical reactions in the cell (metabolic pathways) that are blocked by antimicrobials.
Transmission of resistant organisms occurs by the same mechanisms as for their non-resistant relatives, but is more likely to occur in certain settings. For example, infection by methicillin-resistant Staphylococcus aureus happens more commonly in hospital intensive-care units and long-term care facilities. Methicillin-resistant S. aureus has also been detected on pets, having probably been transmitted to them by humans, and may be transmitted back to humans from these animals. It has not been detected in food animals.
IN CONTEXT: REAL-WORLD RISKS
Acquired adaptation of bacteria to many antibiotics has become a problem since the early 1990s. For example, many hospitals now must cope with the presence of methicillin-resistant Staphylococcus aureus (MRSA), which displays resistance to almost all currently used antibiotics. Dealing with infections caused by MRSA and other resistant organisms requires increased hospital staff hours, increased supplies, and can restrict the availability of hospital beds when cohorting (grouping together patients with the same disease) or isolation is necessary.
The few antibiotics to which antibiotic-resistant bacteria do respond tend to be expensive, with few options for delivery. For example, the drug meropenum is sometimes prescribed for persons with pneumonia, meningitis, or serious skin infections that are caused by organisms that are resistant to common antibiotics. Meropenum can be delivered by intravenous injection or infusion only, and is two to three times more expensive than the commonly prescribed antibiotics for these conditions.
Additionally, disease-causing organisms can sometimes adapt so that they are able grow and multiply on solid surfaces. This mode of growth is called a biofilm. A biofilm environment induces many changes in growing bacteria, some of which involve the expression of previously unexpressed genes and deactivation of actively expressing genes. The structure of the biofilm and these genetic changes often make the bacteria extraordinarily resistant to many antibiotics. Biofilms sometimes occur on some hospital surfaces and in implanted devices such as artificial joints and long-term intravenous access catheters.
Resistant organisms are most common in settings where antimicrobial drugs are most widely used. They are therefore most often encountered in industrialized countries. In the United States, for example, about a third of all Staphylococcus aureus infections are now methicillin-resistant. Certain organisms that are found and treated almost exclusively in developing countries, such as the malaria parasite, have evolved resistant varieties in those regions.
When doctors find that they are trying to treat an infection by a resistant organism, they use trial and error to find a drug to which the organism is not resistant. This process usually involves trying one drug after another, starting with those that are least toxic for the patient and most specific for the target organism, and working towards drugs that are less desirable or potentially produce greater side effects. Even when a drug that works is found—and some organisms are now resistant to all the agents used against them—the delay involved in this process is dangerous to the patient.
The U.S. Centers for Disease Control (CDC) has stated that antibiotic resistance is a key microbial threat to health in the United States. The CDC launched a National Campaign for Appropriate Antibiotic Use in the Community in 1995, which was renamed in 2003 as Get Smart: Know When Antibiotics Work. This campaign seeks to slow the evolution of antibiotic resistance primarily by discouraging the unnecessary use of anti-biotics for upper respiratory infections. Seventy-five percent of antibiotics prescribed by office-based physicians are for upper respiratory infections, most of which are viral and therefore unaffected by antibiotics.
Antimicrobial resistance has become a major public health concern in recent years. According to the U.S. National Institute of Allergies and Infectious Diseases, tuberculosis, gonorrhea, malaria, and childhood ear infections are all more difficult to treat today, because of antimicrobial resistance, than they were a few decades ago. Chloroquine resistance evolved by the malaria parasite threatens millions of lives: since 1978, chloroquine resistance has been reported in all tropical African countries, becoming more common in recent decades. The impact on public health has been major, with malaria deaths doubling or tripling in some African countries. In Senegal, child deaths from malaria have increased by up to a factor of 6 with the growth of chloroquine resistance. All alternatives to chloroquine are more expensive and have comparatively severe side effects.
One of the most contentious aspects of antimicrobial resistance today is the use of antibiotics in agriculture. Millions of pounds of antibiotics are fed to livestock annually in the United States and elsewhere, mostly as growth promoters. Studies over the last several decades have shown that this promotes the evolution of resistant organisms. In 2005, the U.S. Food and Drug Administration banned the use enrofloxacin (an antibacterial) in poultry. The European Union has banned the use of a range of almost all growth-promoting hormones and antimicrobials in agriculture.
Some experts also warn that the nearly universal use of antimicrobial household soaps may contribute to the evolution of resistant organisms. Ordinary soap and water wash bacteria away rather than killing them directly and so do not provide selective pressure for evolution of resistance. Moreover, studies in India have found that antimicrobial soaps do not improve health any more than old-fashioned soaps.
Phage therapy—the use of certain viruses to infect and kill bacteria—shows some promise as an alternative strategy for treating infections by multiply resistant organisms, and research continues in this area.
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