Staphylococcus aureus (SA)—Antibiotic Resistance (General) Throughout history, Staphylococcus aureus (SA) has been a dangerous pathogen once it has successfully breached the normal defense system. The first effective antibiotic against SA, penicillin, became available in the 1940s. Soon after, SA evolved resistance to penicillin, and by the late 1950s, 50 percent of all SA were resistant. Today, fewer than 10 percent of SA infections can be cured with penicillin.
The next weapons against SA, methicillin and cephalosporins, became available in the 1960s and 1970s. By the late 1970s, some strains of SA had evolved resistance to these drugs. Today, as many as 50 percent of SA isolated from U.S. hospitals are resistant to methicillin.
The last effective defense against methicillin-resistant SA (called MRSA) is vancomycin. However, the increasing use of vancomycin has set the stage for the evolution of vancomycin-resistant SA (called VRSA). Antibiotic use and resistance represent a vicious cycle: The more doctors use vancomycin, the more they create an environment that encourages the evolution of VRSA.
Staphylococcus aureus (SA)—Antibiotic Resistance (MRSA) MRSA, or methicillin-resistant Staphylococcus aureus, are strains of the bacterial pathogen Staphylococcus aureus (SA) that have evolved resistance to the antibiotic methicillin. These strains are also likely to be resistant to other antibiotics used to treat SA infections. MRSA strains first appeared in the late 1970s and currently 40-50 percent of SA isolated from U.S. hospitals are resistant to methicillin. These infections are treated with the powerful antibiotic vancomycin. Scientists hypothesize that the strains of SA most likely to evolve resistance to vancomycin are the MRSA.
Staphylococcus aureus (SA)—Antibiotic Resistance (VRSA) Scientists expect strains of the bacterium Staphylococcus aureus (SA) that are fully resistant to the antibiotic vancomycin to evolve soon. Vancomycin-resistant Staphylococcus aureus (VRSA) is the term used to describe these strains. The expected emergence of VRSA is alarming because vancomycin is the only antibiotic that is effective against MRSA, strains of SA that are resistant to the antibiotic methicillin (MRSA).
Although VRSA—strains of SA that are fully resistant to vancomycin—do not currently exist, medical workers have recently isolated strains of SA that are four times more resistant to vancomycin than SA strains found previously. Because infections due to these strains do not respond to the usual doses of vancomycin, many physicians and other experts incorrectly refer to them as VRSA. They should be described as SA strains with intermediate resistance to vancomycin. Infections due to these strains can be cured using higher doses of vancomycin.
Staphylococcus aureus (SA)—Definition Staphylococcus aureus (SA) is a bacterium that is commonly found on the skin and in the eyes, nose, and throat of animals and humans. SA is one of the most common causes of infections worldwide. Though not a problem for healthy adults, SA is potentially virulent and can cause serious infections of the skin, eyes, brain, blood, and respiratory and digestive tracts, as well as bone and connective tissue. Some SA infections, such as bacteremia, have death rates of 40 percent.
Staphylococcus aureus (SA)—Risk Factors Although the body's defenses must be weakened or breached before Staphylococcus aureus (SA) bacteria cause disease, many people are potential victims of SA infections. SA enters the body through wounds such as burns, deep cuts, or surgical incisions. People whose immune systems are weakened from bouts with other diseases—hospital patients with influenza, leukemia, skin disorders, or diabetes, or patients recovering from kidney transplants—are vulnerable. Patients receiving radiation or chemotherapy also are more susceptible to SA infection. In 1992, nearly 1 million of the 23 million U.S. citizens who had surgery developed infections, most of them due to SA. Likewise, SA poses a threat to newborns, whose immune systems are not yet fully functioning.
Staphylococcus aureus (SA)—Transmission Because Staphylococcus aureus (SA) bacteria can survive dry conditions, they remain alive for long periods of time on dust particles, clothing, furniture, or hospital equipment. SA is able to grow with or without oxygen. This allows the bacteria to survive the aerobic conditions of the skin or nasal passages, waiting for an opportunity to invade deeper tissues. Once inside, SA can produce powerful toxins that further destroy and disrupt the body's tissues. SA can also resist immune system cells that engulf and destroy invading bacteria, making it a formidable adversary for the immune system.
A high percentage of hospital workers are passive carriers for SA, harboring the bacteria on their skin and in their upper respiratory tracts without showing any symptoms. For this reason, SA often spreads from patient to patient via the hands of hospital workers. SA also spreads via dust, clothing, furniture, or medical equipment that has been in contact with infected patients.
Antibiotic Resistance—Cost As more and more strains of disease-causing bacteria become resistant to commonly used antibiotics, physicians must switch to other, often more expensive drugs. For example, switching from the penicillins to methicillin in the treatment of Staphylococcus aureus (SA) infections increased treatment costs about 10-fold.
It is difficult to assess the overall cost of antibiotic resistance. A report from the Government Accounting Office indicates that no federal agency adequately monitors antibiotic resistance or evaluates its social and financial costs. One estimate, however, places the annual cost of antibiotic resistance as high as $5 billion per year.
Antibiotic Resistance—Definition Antibiotic resistance describes the condition of bacteria whose growth and reproduction is unaffected by particular antibiotics. Bacteria have a variety of mechanisms for evading the toxic effects of antibiotics. In some cases, the bacterial cell membranes are altered so that an antibiotic cannot enter the cell. In other cases, resistant bacteria actively pump the antibiotic out of the cell as soon as it enters. Still other resistant bacteria make an enzyme that degrades an antibiotic as soon as it enters the cell. There are also other mechanisms for antibiotic resistance.
Mutations in genes that code for particular proteins may result in antibiotic resistance. For example, if an antibiotic uses a particular protein in the cell membrane to enter the cell, a change in that protein (due to a mutation in the gene that codes for it) may prevent the antibiotic from entering the cell. Many genes that result in antibiotic resistance are found on DNA molecules that are easily transferred from one bacterium to another.
Antibiotic Resistance—Evolution Antibiotic resistance in bacteria evolves by mutations in the bacterium's genes, by rearrangement of the bacterium's genes, or by acquisition of genes that result in antibiotic resistance from other bacteria. Regardless of the way a bacterium becomes resistant to a particular antibiotic, once this has happened, a vicious cycle begins. The resistant bacterium will survive treatment while most of the susceptible bacteria in the population die. After antibiotic treatment is completed, the few surviving susceptible bacteria and the resistant bacterium will reproduce, and the resistant bacterium will pass the gene that provides antibiotic resistance on to its progeny. If the infection recurs, there will now be a larger number of antibiotic-resistant bacteria in the population. Antibiotic treatment will be less successful or may fail completely. Across time, almost all of the bacteria of that type that people encounter will be resistant to the particular antibiotic, and new (and, in many cases, more expensive) antibiotics must be used to treat infections caused by that kind of bacteria.
Antibiotic Resistance—Prevention (Challenges) Overuse of antibiotics has increased the numbers of antibiotic-resistant bacteria. The Centers for Disease Control and Prevention (CDC) estimates that half of the 100 million courses of antibiotics prescribed annually are unnecessary. This misuse means that bacteria will evolve resistance to common antibiotics sooner, and that doctors will have to use last-resort antibiotics such as vancomycin more and more. Therefore, to delay the development of antibiotic-resistant organisms, the CDC has developed a set of recommendations for appropriate use of antibiotics.
Nevertheless, following the CDC recommendations is challenging. One survey of pediatricians revealed that, during a one-month period, 96 percent of pediatricians polled had been pressured by patients to prescribe antibiotics, even when they were not needed. Another study found that, despite education about appropriate uses of the antibiotic vancomycin, 40-60 percent of vancomycin treatments did not follow the CDC recommendations.
Another challenge for preventing antibiotic resistance is that restrictions on the use of one antibiotic often lead to increases in the use of others. In one hospital, restrictions on the use of the antibiotic cephalosporin not only decreased the incidence of cephalosporin-resistant bacteria but also increased the use of another antibiotic (imipenem). Thus, the number of bacteria resistant to that antibiotic increased.
Antibiotic Resistance—Prevention (Successful Programs) Several initiatives are under way to promote more careful uses of antibiotics. One hospital in Arkansas created a program to wipe out enterococcal bacteria that are resistant to vancomycin (called vancomycin-resistant enterococci, or VRE) by using strict containment protocols as well as extensive education of staff. For example, some effective precautions can be as simple as handwashing. Though some staff complained that the program was overly complicated and labor intensive, rates of VRE infection declined and the last case of VRE at that hospital was reported in May 1998.
Antibiotic Resistance—Research (Development Costs) Pharmaceutical companies spend an average $500 million and 12-15 years doing initial research to design a drug, developing large-scale production of it, conducting clinical trials of the drug's safety and effectiveness, and bringing the drug to market.
Vancomycin-Resistant SA (VRSA)—Definition The term vancomycin-resistant Staphylococcus aureus, or VRSA, describes strains of Staphylococcus aureus (SA) bacteria that are resistant to doses of the antibiotic vancomycin at or above 32 micrograms per milliliter. Strains of SA that are killed by doses of vancomycin less than or equal to 4 micrograms per milliliter are considered susceptible to the antibiotic, whereas strains that require vancomycin doses of 8 to 16 micrograms per milliliter for killing are considered to have intermediate levels of resistance.
No strains of VRSA have yet appeared; however, since mid-1996, physicians in Japan, the United States, and Europe have described several cases of SA infections that required vancomycin doses of at least 8 micrograms per milliliter to cure the infection. Some medical workers have inaccurately called these strains of bacteria VRSA; however, they are actually SA with intermediate levels of vancomycin resistance.
Vancomycin-Resistant SA (VRSA)—Diagnosis Emerging vancomycin-resistant Staphylococcus aureus (VRSA) bacterial infections would likely have similar symptoms to Staphylococcus aureus (SA) infections, except that the infection would persist after vancomycin drug therapy. Doctors test for vancomycin resistance by taking samples of bacteria from an SA infection, culturing or growing them, and measuring their growth in media containing various levels of vancomycin. SA that are killed by vancomycin at a concentration of 4 micrograms per milliliter are considered susceptible, those that require 8 to 16 micrograms per milliliter for killing are considered to have intermediate resistance, and those that are resistant to vancomycin concentrations at or above 32 micrograms per milliliter are considered fully resistant to the drug. To date, the most resistant SA strains show intermediate rather than full resistance to vancomycin.
Vancomycin-Resistant SA (VRSA)—Evolution In bacteria, antibiotic resistance evolves by mutations in their genes, by rearrangement of their genes, or by acquiring genes that provide antibiotic resistance from other bacteria. The strains of Staphylococcus aureus (SA) bacteria that have intermediate resistance to vancomycin appear to be the result of mutations in their genes. However, scientists are concerned that SA might also acquire genes for full vancomycin resistance from other bacteria, specifically, vancomycin-resistant enterococci (VRE).
Enterococci are a group of bacteria closely related to Staphylococcus species, but they are less virulent than SA. When the first VRE strains appeared in 1986, they spread rapidly through hospitals. Currently about 25 percent of enterococci isolated in U.S. hospitals are VRE. Scientists are especially concerned about VRE because these bacteria could potentially transfer the genes that make them resistant to vancomycin to other species of bacteria. Because of their close relationship, it is highly likely that vancomycin-resistance genes will spread from VRE to SA. Laboratory experiments have already confirmed this possibility.
Vancomycin-Resistant SA (VRSA)—Incidence (Intermediate Resistance) As of 1999, there have been several cases of Staphylococcus aureus (SA) bacterial infections with intermediate resistance to the antibiotic vancomycin reported. The first case was reported in 1996 in Japan, when vancomycin failed to cure a four-month-old boy who became infected with SA after heart surgery. Despite 29 days of vancomycin therapy, the infection persisted. Although doctors finally stopped the infection using a combination of different antibiotics, they understood that a barrier had been crossed. One researcher underscored the urgency of the situation: "S. aureus, a major cause of hospital-acquired infections, has thus moved one step closer to becoming an unstoppable killer."
Since that time, three independent cases of SA with intermediate resistance to vancomycin have occurred in the United States: in Michigan, New York, and New Jersey. In these patients, doctors resorted to alternative antibiotics. Although they eliminated the infection in two of the patients, all the patients eventually died. (All of these patients were quite ill, so the infection might not have been the critical factor in their deaths.) Individual cases of SA with intermediate resistance have also cropped up in France and Hong Kong.
Vancomycin-Resistant SA (VRSA)—Incidence (Predictions) There have been only a handful of confirmed cases of Staphylococcus aureus (SA) with intermediate resistance to the antibiotic vancomycin. But researchers fear it is only a matter of time until strains of SA that are fully resistant to vancomycin (vancomycin-resistant SA, or VRSA) appear. VRSA will probably appear first in developed countries with the highest rates of vancomycin use, such as the United States.
Although there is no way to predict exactly when VRSA will appear or how rapidly it will spread, researchers can make reasonable estimates using a parallel case: the evolution of vancomycin-resistant enterococci (VRE). Enterococci are harmful bacteria closely related to staphylococci. Until the late 1980s, most enterococci were susceptible to vancomycin. The first case of VRE was reported in 1986 in Europe and then another in 1988 in the United States. Then, between 1989 and 1993, the number of VRE cases in hospital patients increased 20-fold. In New York City in 1993, 97 percent of clinical labs had found at least one strain of VRE. By 1994, 61 percent of hospitals nationwide had reported cases of VRE.
Vancomycin-Resistant SA (VRSA)—Prevention In 1995, the Centers for Disease Control and Prevention (CDC) published recommendations for use of the antibiotic vancomycin use in order to prevent the rapid spread of vancomycin resistance among bacteria. It emphasized the importance of wise use of vancomycin, continuing education for health care providers on prevention and control, and active screening and microbiological testing for resistant strains. The CDC recommends that vancomycin use be restricted to
Treatment of serious infections due to bacteria resistant to certain antibiotics such as methicillin. Treatment of serious infections due to bacteria in patients who have serious allergies to antibiotics such as methicillin. Treatment of antibiotic-associated colitis (an inflammation of the colon) that fails to respond to standard treatment or that is severe and life threatening. Prevention of endocarditis (an infection of heart tissue) following certain procedures in patients at high risk for endocarditis. Preventative surgical procedures involving implants at hospitals that have a high rate of infection due to methicillin-resistant Staphylococcus aureus (MRSA). In this case, treatment should be discontinued after a maximum of two doses. Vancomycin-Resistant SA (VRSA)—Research (Promising Therapies) Research continues along several lines to develop new therapies to cure infections that are caused by emerging Staphylococcus aureus bacteria that are resistant to the antibiotic vancomycin (called VRSA). Some researchers hope to improve the effectiveness of vancomycin by modifying its structure. One promising experiment showed that a subpart of the vancomycin molecule killed bacteria 10 times better than the whole molecule does. Other modifications to vancomycin may produce additional, effective antimicrobial drugs.
Another promising therapy uses synthetic peptides (short protein molecules) to block the release of toxins produced by Staphylococcus aureus (SA). One of the reasons that SA is so virulent is that it produces potent toxins. If the release of the toxins is prevented, much of the damage caused by SA is also prevented. The peptides bind to a receptor on the surface of the SA bacterium that controls the release of toxins. In preliminary tests, researchers have used synthetic peptides to reduce toxin release, curing mice infected with SA. Even though the peptides do not kill the bacteria, by preventing the damage caused by SA they could give patients' immune systems enough of an edge to knock out the infection. Research is needed to bring such a therapy to reality.
Other research studies may lead to the development of effective vaccines against SA or the toxins it produces. Scientists are currently testing yet another strategy. To slow the growth of virulent strains of SA, they infect patients with a non-disease-causing strain of SA. The hope is that the non-disease-causing strain will crowd out the virulent strain.
Vancomycin-Resistant SA (VRSA)—Risk Factors People at the greatest risk from infections caused by emerging Staphylococcus aureus that are resistant to the antibiotic vancomycin (called VRSA) are the same as those at risk from the usual Staphylococcus aureus (SA) bacteria: people who have weak immune systems due to injury, illness, or age (either very young or very old). At particular risk will be hospital patients, because their health is already compromised and they are more likely to encounter VRSA in hospitals. Because of the increased risk, a VRSA epidemic might discourage people from having elective surgeries and make nonelective surgery more risky.
Vancomycin-Resistant SA (VRSA)—Vancomycin (Definition) Vancomycin is a naturally occurring compound, derived from a fungus. It is also an antibiotic-of-last-resort: Vancomycin is the only drug effective against infections caused by strains of Staphylococcus aureus (SA) that are resistant to all of the other drugs that previously cured SA infections.
Scientists do not know precisely how vancomycin kills bacteria. They hypothesize that it interferes with cell wall formation. A bacterium without an intact cell wall is likely to rupture during growth and cell division; thus, any drug that prevents or disturbs cell wall formation will kill the bacterium.
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