Resistance to last-line antibiotic makes bacteria resistant to immune system
Bacteria resistant to the antibiotic colistin are also commonly resistant to antimicrobial substances made by the human body, according to a study in mBio®, the online open-access journal of the American Society for Microbiology. Cross-resistance to colistin and host antimicrobials LL-37 and lysozyme, which help defend the body against bacterial attack, could mean that patients with life-threatening multi-drug resistant infections are also saddled with a crippled immune response. Colistin is a last-line drug for treating several kinds of drug-resistant infections, but colistin resistance and the drug’s newfound impacts on bacterial resistance to immune attack underscore the need for newer, better antibiotics.
Corresponding author David Weiss of Emory University says the results show that colistin therapy can fail patients in two ways. “The way that the bacteria become resistant [to colistin] allows them to also become resistant to the antimicrobials made by our immune system. That is definitely not what doctors want to do when they’re treating patients with this last line antibiotic,” says Weiss.
Although it was developed fifty years ago, colistin remains in use today not so much because it’s particularly safe or effective, but because the choices for treating multi-drug resistant Acinetobacter baumannii and other resistant infections are few and dwindling. Colistin is used when all or almost all other drugs have failed, often representing a patient’s last hope for survival.
Weiss says he and his colleagues noted that colistin works by disrupting the inner and outer membranes that hold Gram-negative bacterial cells together, much the same way two antimicrobials of the human immune system, LL-37 and lysozyme, do. LL-37 is a protein found at sites of inflammation, whereas lysozyme is found in numerous different immune cells and within secretions like tears, breast milk, and mucus, and both are important defenses against invading bacteria. Weiss and his collaborators from Emory, the CDC, Walter Reed Army Institute of Research, and Grady Memorial Hospital in Atlanta set out to find whether resistance to colistin could engender resistance to attack by LL-37 or lysozyme.
Looking at A. baumannii isolates from patients around the country, they noted that all the colistin-resistant strains harbored mutations in pmrB, a regulatory gene that leads to the modification of polysaccharides on the outside of the cell in response to antibiotic exposure. Tests showed a tight correlation between the ability of individual isolates to resist high concentrations of colistin and the ability to resist attacks by LL-37 or lysozyme.
This was very convincing, write the authors, that mutations in the pmrB gene were responsible for cross-resistance to LL-37 and lysozyme, but to get closer to a causative link between treatment and cross-resistance, they studied two pairs of A. baumannii isolates taken from two different patients before and after they were treated for three or six weeks with colistin. The results helped confirm the cross-resistance link: neither strain taken before treatment was resistant to colistin, LL-37, or lysozyme, but the strains taken after treatment showed significant resistance to colistin and lysozyme. (One post-colistin isolate was no more or less resistant to LL-37 than its paired pre-colistin isolate.) Like the resistant strains tested earlier, both post-colistin isolates harbored crucial mutations in the pmrB gene that apparently bestow the ability to resist treatment.
How does resistance spread?
“Antibiotic resistance is an inevitable consequence of [antibiotic] use, the more you use them the more resistance you will get.” Says Associate Professor Collignon.
As well as the transfer of antibiotic resistance genes directly from one bacterium to another, resistance also spreads through the movement of bacteria from one host to another either directly or indirectly, for example, through food, water or even contact between animals - including humans.
Antibiotics, like herbicides or pesticides, select for antibiotic resistant bacteria. When an antibiotic attacks a particular bacterial infection there is always the chance that, within a population of bacteria, there will be some members with resistance. Those not killed are now free to multiply without any competition from the sensitive strains. Antibiotics can also wipe out friendly bacteria, which would otherwise compete with the resistant strain for resources.
And to make matters worse, antibiotics can also increase resistance emerging in harmless bacteria which can, under certain conditions such as in an immune suppressed patient, become aggressive and cause infection. Just the existence of antibiotic resistant bacteria, harmful or not, increases the likelihood of resistance being passed on to other bacteria.
Resistance is a natural phenomenon perhaps as old as bacterium themselves. However, we have contributed to an increase in the rate of antibiotic resistance through the increased transmission of infection and the misuse and abuse of antibiotics.
The authors point out that the apparent link between resistance to colistin and cross-resistance to antimicrobial agents of the immune system could well extend to other pathogens that are treated with colistin, including Pseudomonas aeruginosa and Klebsiella pneumoniae. Weiss says he plans to follow up with studies to determine whether this bears out.
For Weiss, the problems with colistin are symptomatic of a much larger trio of problems: increasing levels of drug resistance, cuts in federal funding for antibiotic research, and lack of incentives for pharmaceutical companies to invest in antibiotic R&D. “We don’t have enough antibiotics, and it’s really important for the research community and the public to support increases in funding for research to develop new antibiotics,” says Weiss.
Bacterial Resistance to Antibiotics
In the past 60 years, antibiotics have been critical in the fight against infectious disease caused by bacteria and other microbes. Antimicrobial chemotherapy has been a leading cause for the dramatic rise of average life expectancy in the Twentieth Century. However, disease-causing microbes that have become resistant to antibiotic drug therapy are an increasing public health problem. Wound infections, gonorrhea, tuberculosis, pneumonia, septicemia and childhood ear infections are just a few of the diseases that have become hard to treat with antibiotics. One part of the problem is that bacteria and other microbes that cause infections are remarkably resilient and have developed several ways to resist antibiotics and other antimicrobial drugs. Another part of the problem is due to increasing use, and misuse, of existing antibiotics in human and veterinary medicine and in agriculture.
In 1998, in the United States, 80 million prescriptions of antibiotics for human use were filled. This equals 12,500 tons in one year. Animal and agricultural uses of antibiotics are added to human use. Agricultural practices account for over 60% of antibiotic usage in the U.S., so this adds an additional 18,000 tons per year to the antibiotic burden in the environment.
Nowadays, about 70 percent of the bacteria that cause infections in hospitals are resistant to at least one of the drugs most commonly used for treatment. Some organisms are resistant to all approved antibiotics and can only be treated with experimental and potentially toxic drugs. An alarming increase in resistance of bacteria that cause community acquired infections has also been documented, especially in the staphylococci and pneumococci (Streptococcus pneumoniae), which are prevalent causes of disease and mortality. In a recent study, 25% of bacterial pneumonia cases were shown to be resistant to penicillin, and an additional 25% of cases were resistant to more than one antibiotic.
Microbial development of resistance, as well as economic incentives, has resulted in research and development in the search for new antibiotics in order to maintain a pool of effective drugs at all times. While the development of resistant strains is inevitable, the slack ways that we administer and use antibiotics has greatly exacerbated the process.
“We got complacent for a while and the bugs are becoming resistant. This is something we can reverse - or make a lot better - if we have the resources.”
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mBio® is an open access online journal published by the American Society for Microbiology to make microbiology research broadly accessible. The focus of the journal is on rapid publication of cutting-edge research spanning the entire spectrum of microbiology and related fields.
The American Society for Microbiology is the largest single life science society, composed of over 39,000 scientists and health professionals. ASM’s mission is to advance the microbiological sciences as a vehicle for understanding life processes and to apply and communicate this knowledge for the improvement of health and environmental and economic well-being worldwide.
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Jim Sliwa
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202-942-9297
American Society for Microbiology