The Challenge of Antibiotic Resistance Certain bacterial infections now defy all antibiotics. The resistance problem may be reversible, but only if society begins to consider how the drugs affect "good" bacteria as well as "bad" by Stuart B. Levy ........... SUBTOPICS: A Bad Combination My Resistance Is Your Resistance How Antibiotics Promote Resistance Antibiotic Use Is Out of Control Reversing Resistance Considering the Environmental Impact SIDEBARS: The Antibacterial Fad: A New Threat Some Actions Physicians and Last year an event doctors had been fearing finally occurred. In three geographically separate patients, an often deadly bacterium, Staphylococcus aureus, responded poorly to a once reliable antidote--the antibiotic vancomycin. Fortunately, in those patients, the staph microbe remained susceptible to other drugs and was eradicated. But the appearance of S. aureus not readily cleared by vancomycin foreshadows trouble. Worldwide, many strains of S. aureus are already resistant to all antibiotics except vancomycin. Emergence of forms lacking sensitivity to vancomycin signifies that variants untreatable by every known antibiotic are on their way. S. aureus, a major cause of hospital-acquired infections, has thus moved one step closer to becoming an unstoppable killer. The looming threat of incurable S. aureus is just the latest twist in an international public health nightmare: increasing bacterial resistance to many antibiotics that once cured bacterial diseases readily. Ever since antibiotics became widely available in the 1940s, they have been hailed as miracle drugs--magic bullets able to eliminate bacteria ANTIBIOTIC-RESISTANT BACTERIAConsumers Can Take to Limit Resistance ILLUSTRATIONS: Antibiotic-Resistant Bacteria Picking Up Resistance Genes Resistant Population A Pharmaceutical Strategy FURTHER READING RELATED LINKS without doing much harm to the cells of treated individuals. Yet with each passing decade, bacteria that defy not only single but multiple antibiotics--and therefore are extremely difficult to control--have become increasingly common. What is more, strains of at least three bacterial species capable of causing life-threatening illnesses (Enterococcus faecalis, Mycobacterium tuberculosis and Pseudomonas aeruginosa) already evade every antibiotic in the clinician's armamentarium, a stockpile of more than 100 drugs. In part because of the rise in resistance to antibiotics, the death rates for some communicable diseases (such as tuberculosis) have started to rise again, after having declined in the industrial nations. How did we end up in this worrisome, and worsening, situation? Several interacting processes are at fault. Analyses of them point to a number of actions that could help reverse the trend, if individuals, businesses and governments around the world can find the will to implement them. One component of the solution is recognizing that bacteria are a natural, and needed, part of life. Bacteria, which are microscopic, single-cell entities, abound on inanimate surfaces and on parts of the body that make contact with the outer world, including the skin, the mucous membranes and the lining of the intestinal tract. Most live blamelessly. In fact, they often protect us from disease, because they compete with, and thus limit the proliferation of, pathogenic bacteria--the minority of species that can multiply aggressively (into the millions) and damage tissues or otherwise cause illness. The benign competitors can be important allies in the fight against antibiotic-resistant pathogens. People should also realize that although antibiotics are needed to control bacterial infections, they can have broad, undesirable effects on microbial ecology. That is, they can produce long-lasting change in the kinds and proportions of bacteria--and the mix of antibiotic-resistant and antibiotic-susceptible types--not only in the treated individual but also in the environment and society at large. The compounds should thus be used only when they are truly needed, and they should not be administered for viral infections, over which they have no power. A Bad Combination Although many factors can influence whether bacteria in a person or in a community will become insensitive to an antibiotic, the two mainforces are the prevalence of resistance genes (which give rise to proteins that shield bacteria from an antibiotic's effects) and the extent of antibiotic use. If the collective bacterial flora in a community have no genes conferring resistance to a given antibiotic, the antibiotic will successfully eliminate infection caused by any of the bacterial species in the collection. On the other hand, if the flora possess resistance genes and the community uses the drug persistently, bacteria able to defy eradication by the compound will emerge and multiply. Antibiotic-resistant pathogens are not more virulent than susceptible ones: the same numbers of resistant and susceptible bacterial cells are required to produce disease. But the resistant forms are harder to destroy. Those that are slightly insensitive to an antibiotic can often be eliminated by using more of the drug; those that are highly resistant require other therapies. To understand how resistance genes enable bacteria to survive an attack by an antibiotic, it helps to know exactly what antibiotics are and how they harm bacteria. Strictly speaking, the compounds are defined as natural substances (made by living organisms) that inhibit the growth, or proliferation, of bacteria or kill them directly. In practice, though, most commercial antibiotics have been chemically altered in the laboratory to improve their potency or to increase the range of species they affect. Here I will also use the term to encompass completely synthetic medicines, such as quinolones and sulfonamides, which technically fit under the broader rubric of antimicrobials. Whatever their monikers, antibiotics, by inhibiting bacterial growth, give a host's immune defenses a chance to outflank the bugs that remain. The drugs typically retard bacterial proliferation by entering the microbes and interfering with the production of components needed to form new bacterial cells. For instance, the antibiotic tetracycline binds to ribosomes (internal structures that make new proteins) and, in so doing, impairs protein manufacture; penicillin and vancomycin impede proper synthesis of the bacterial cell wall. Certain resistance genes ward off destruction