The full extent of the problem is not known, since no nation has a satisfactory means of monitoring the spread of resistance, according to the Institute of Medicine, a branch of the U.S. National Academy of Sciences. But a growing body of evidence suggests that resistance is already a major medical burden. In the United States, for example, it is estimated that drug-resistant bacteria now cause about 70 percent of the 90,000 fatal hospital infections that occur every year. The total cost of drug-resistant infection in the United States is now thought to exceed $30 billion. Resistance may be a more noticeable threat in the industrialized world, where it is causing a resurgence of diseases that had been largely suppressed. But with many diseases, the effects will likely be far worse in poorer countries.
One of the most threatening developments involves tuberculosis, the respiratory disease that infects 7.3 million people every year, and kills 2.9 million. One-sixth of all known strains of TB now show some degree of resistance, and resistant strains of the disease occur all over the world. But the problem is at its worst in Russia, where extremely severe forms of multidrug-resistant TB - called "MDR-TB" - have broken out in recent years. Of the 109,000 new cases of tuberculosis that Russia sees every year, an estimated 7 percent are MDR-TB. In Russian prisons, which are a principal breeding ground for the disease, MDR-TB may now account for as many as 20 percent of all new cases. Some 3.5 million Russians may contract MDR-TB by the close of the year 2000, and public health officials regard its spread elsewhere as inevitable. Last year an international panel of physicians who toured Siberian prisons and hospitals called for $100 million in emergency international aid to control the incipient epidemic. According to the visiting physicians, MDR-TB now constitutes "a direct, global public health threat."
Malaria is also showing increased resistance. Malaria is caused by a blood parasite, which is present in 300 to 500 million people and kills 1.5 to 2.7 million of them every year. Some 90 percent of all malaria infections occur in Africa, as do 90 percent of all malaria deaths. But for reasons that remain obscure, the center for malaria resistance is in western Thailand, along the border with Myanmar. It was in this area in the 1950s that doctors began to encounter resistance to quinine, the first effective and widely available malaria drug. This was also the area where quinine's successor, chloroquine, was first defeated. (Malaria in most parts of the world is now resistant to both drugs.) The standard malaria drug today is mefloquine, but by 1996 infections in western Thailand were showing a 50 percent resistance to that drug too. Among infected children, the rate was running at 80 percent. A drug called doxycycline is now recommended for travel into the area. One of the most effective local standbys is actually a very old remedy: artesunate, a medication derived from a traditional Chinese herbal remedy. But given the rate at which the local swains are evolving resistance, it is conceivable that western Thailand could one day produce a strain of wholly untreatable malaria.
Medically advanced societies are breeding huge resistance problems as well. The United States, Japan, England, and France have all now seen strains of the bacterium Staphylococcus aureas that are resistant to vancomycin, generally regarded as the antibiotic of last resort. Staph species are ubiquitous and typically colonize the human skin and nostrils. But while generally harmless on the skin, staph can cause blood infections if it enters the body through cuts, scrapes, or medical procedures. Staph is responsible for most hospital infections and it is estimated that more than 90 percent of staph aureas strains now show resistance to virtually all antibiotics except for vancomycin. Given the current spectrum of available drugs, widespread staph resistance to vancomycin would essentially remove the safety net that underlies all invasive medical procedures, from open heart surgery to the insertion of a simple intravenous drip.
Resistant strains of HIV, the virus that causes AIDS, have also emerged in the industrialized countries. Between 30 and 50 percent of all patients undergoing intensive drug therapy for HIV infection now show some degree of resistance. But resistance is not a critical factor in the AIDS pandemic, since over 90 percent of the 34 million people who have the virus live in the developing world, where very few people can afford the medicines in the first place. (Even in wealthier countries, HIV is generally far more prevalent in the poorest populations, which are least likely to have access to the drugs.)
AIDS may, however, play a role in spreading resistant strains of other diseases. Because it compromises its victims' immune systems, epidemic HIV may open a population up to other pathogens, thereby giving their resistant strains more "room for maneuver." In Africa, for example, the high death toll from malaria may result in part from overlapping infections of HIV. It's also possible that with some diseases, HIV infection may somehow directly encourage the development of resistance. French researchers reported last December that they had found resistance to lamivudine, a drug used to treat hepatitis B, in 19 patients infected both with that disease and HIV.
The resistance dilemma results essentially from the power of the drugs themselves. A potent drug may wipe out most of the germs in an infection, but it offers a huge opportunity to any that survive. The remnant population will have plenty of space to multiply and to test itself against the drug. Microorganisms multiply rapidly - bacteria, for example, may go through 9 or 10 generations in a single day. So if many people are fighting the same infection with the same drug, there's a fair chance that the microbe will stumble into a useful mutation, even over a fairly short time. Over the long-term, such an event is virtually inevitable.
But according to many experts, the current crisis could largely have been avoided, because so much of it results from unnecessary use of antibiotics. In the United States, for example, at least half of the antibiotic medication taken annually is "unnecessary or inappropriate," according to Stuart Levy, a professor of microbiology at Tufts University and a leading authority. on the problem. Authorities on resistance say that doctors frequently write prescriptions "on a hunch" - before a firm diagnosis is made - or give in to patients' demands for antibiotics, even when there is no evidence for bacterial infection. Antibiotics are also increasingly being used in products besides medications: toothpaste, soap, even floor cleaners now include antibiotics. More than 50 million pounds of antibiotics are produced every year in the United States alone. The vast quantifies of antibiotics pouting into the bacterial word have greatly boosted the "selection pressure" for adaptation, accelerating the rates at which bacteria adapt to the drugs.
In developing countries, medical and legal oversight is often much more limited and overmedication may be even more pervasive - among people who can afford the drugs. (Some 2.5 billion people, or 40 percent of the world's population, have no access to western medication, and must rely entirely on herbal and other folk remedies.) Overmedication is likely to be exacerbated where manufacturers engage in aggressive promotion of their products, especially in the case of multinational drug companies, which are the most likely conduits for the newer drugs. In China, for example, it is reportedly standard procedure for foreign drug companies to pay doctors and hospital administrators commissions or outright kickbacks for dispensing their products, even though such payments contravene both Chinese law and international pharmaceutical industry codes. China does allow its hospitals to profit from the sale of medicine, and drug sales now account for 60 to 80 percent of hospital revenue in that country. Foreign pharmaceuticals are by far the most lucrative sector of that trade.
Agriculture is another breeding ground for resistance. Antibiotics are sometimes used as pesticides, to control bacterial infection on fruit crops, for example. But the primary agricultural use of the drugs is in livestock. In the United States, over 40 percent of antibiotic production is destined for livestock. And the drugs involved are by and large the same ones used to treat people. Heavy antibiotic use has become an essential part of large-scale, factory farms, in which huge numbers of animals are confined in very close quarters - a condition highly conducive to disease. In the Netherlands, Belgium, and Germany, for example, massive hog operations have produced the densest pig populations in the word: up to 9,000 animals per square kilometer. Europe has seen four major outbreaks of Classical Swine Fever this decade. One recent outbreak, in the Netherlands in 1997, killed or forced the killing of some 6 million pigs and caused over $660 million in losses. Of the 15 livestock diseases considered serious enough to require international monitoring, nine have broken out in Europe since 1984, six of them in epidemic form.
A substantial share of livestock antibiotic use, however, is not intended to treat outbreaks - it's used to promote weight gain by suppressing bacterial colonies that would not necessarily have resulted in disease. In the United States, slightly more than half of livestock antibiotic dosage is probably administered for this reason. Resistance in human diseases has "clearly occurred" as a result of this type of antibiotic use, according to a report issued last July by an expert panel convened by the U.S. National Research Council and the Institute of Medicine. The panel concluded that there was not sufficient evidence to know how extensive the problem was, but it estimated that 40 to 80 percent of the antibiotics used in U.S. livestock production is unnecessary.
Scientists are discovering that heavy, widespread use of antibiotics affects the ecology of disease in several ways. In both people and animals, overexposure to antibiotics tends to eliminate harmless bacteria, making colonization by pathogens more likely. It also knocks out less virulent strains of the pathogens themselves. In poultry production, for example, this mechanism sometimes contributes to a vicious circle in which the antibiotics interrupt the natural bacterial flow from hen to chick, thereby, rendering the chick more susceptible to infection, and further increasing the ostensible need for antibiotics.
Among the bacteria themselves, resistance is a fluid and mobile asset. Different species of bacteria can "talk" to each other by exchanging snippets of DNA in a number of ways. So one pathogen may sometimes transmit its resistance to another. And a genetic adaptation that confers resistance to one drug may work against several. For example, the use of an antibiotic called avoparcin in pig and poultry production has bred strains of enterococcus, a group of blood-poisoning bacteria, that resist not only avoparcin but vancomycin, the current antibiotic of last resort.
And unfortunately, resistance may continue long after exposure to a drug has ceased, a characteristic that could prevent successful reintroduction of an old antibiotic. In one study, for example, researchers in Atlanta, Georgia, were looking for drug resistance in Escherichia coli, a standard part of the human intestinal flora. They examined the diapers of children at a local daycare center and found strains of the bacterium that were resistant to streptomycin, an antibiotic that had gone out of circulation in the United States some 30 years earlier.
The reason resistance can persist for so long, even in the absence of the drug that stimulated it, is that successful adaptation can become a kind of "package deal." The genetic change that confers resistance may also reduce the efficiency of the bacterium's chemical machinery, thereby stimulating yet more adaptation to bring the germ back up to speed. This compensatory adaptation will tend to "lock in" the resistance trait: a mutation that loses that trait will throw the whole system back out of balance, because the compensatory adaptation won't work properly anymore. So germs that mutate in that direction tend to die off, thereby preserving the population's resistance.
In response to the resistance crisis, the U.S. administration plans to add $25 million to its program for addressing drug-resistant pathogens and other emerging infectious diseases, increasing the program budget by nearly a third. And health officials in both the public and private sectors have begun to look for ways to reduce the number of unnecessary prescriptions. Some U.S. pharmacies and hospital administrators have begun to monitor and second-guess prescriptions for vancomycin, which may be prescribed unnecessarily 30 or 40 percent of the time.
European governments are imposing stronger regulations on agricultural antibiotic use. In 1986, Sweden banned the practice of giving the drugs as growth promotants, and the Swedish experience has shown that such bans are feasible. In the first year after the ban, total farm antibiotic use rose in response to a short-term increase in infections, but it has since dropped to a level 55 percent lower than it was before the ban. The European Union recently approved a ban on four antibiotics in animal feed that will go into effect this July. And in Japan and the United States, some poultry farms are now using a bacterial spray on chicks that is intended to reduce the need for antibiotics. The spray infects chicks with benign bacteria, thereby reducing the likelihood of harmful infections.
The private sector is now also responding to the problem, by scaling up efforts to develop new drugs. As recently as 1990, there was relatively little interest in developing new antibiotics among the major pharmaceutical firms. But by the mid-1990s, and especially after the appearance of resistant forms of enterococcus and staph, the drug companies have rushed back into the business. Hundreds of millions of dollars are now being spent on the development of dozens of new drugs. Much of this effort is essentially trying to extend the current lines of attack by developing new variants of existing drugs. But some of the more ambitious research is looking for classes of chemicals that would be entirely new in the germ-killing arsenal.
One large group of candidate chemicals consists of antibiotic peptides (essentially, very small protein molecules) that can be found inside all sorts of creatures - in shark stomachs, pig intestines, cow tongues, frog skins, even in various insects. Scientists working with these chemicals think that it may be much harder for bacteria to develop resistance to them because, among other things, they kill bacteria in an especially traumatic way. Instead of interfering with the function of, say, an enzyme - a typical mode of action for conventional antibiotics - these peptides puncture bacterial membranes. Mutating a single gene might be enough to render an enzyme-attacking drug ineffective, but changing a structure as complex as a membrane would probably require mutations in many genes. Peptide antibiotics may also be effective against other types of pathogens besides bacteria - perhaps even against viruses. Several peptide antibiotics are moving through clinical trials now.
Development of peptide antibiotics is complicated, however, because the chemicals appear generally to be more toxic than conventional antibiotics. A broader concern with drugs such as these is their potential ecological effect: peptide antibiotics are produced in organisms specifically for fighting infection. So if intense human use does eventually produce resistance, it's worth considering what that will mean for the organisms that produce the compounds naturally. It's conceivable - although perhaps not very likely - that the spread of peptide resistance could alter the relationships between wildlife diseases and their hosts.
Rebuilding the drug arsenal is likely to be a labor of several more years at least, and of course the pathogens aren't holding still in the meantime. Researchers are reporting resistance problems with some drugs that are still in the trial stage. (Such problems are difficult to avoid entirely because extensive testing in animals is usually necessary before a drug can be released for use in humans.) A more fundamental problem, perhaps, is what will happen when any future wonder drugs hit the market. Any really promising new drug is likely to be marketed very aggressively by its manufacturer. The promotion, combined with the world's growing appetite for pills, is likely to hasten the day when the new remedy no longer works.
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|Title Annotation:||evolution of microorganisms to develop strains that are resistant to antibiotics; Environmental Intelligence|
|Date:||Mar 1, 1999|
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