Posted December 21, 2001 · Issue 117

The 1945 Nobel Prize in Physiology or Medicine went to Sir Alexander Fleming, Ernst Boris Chain, and Sir Howard Walter Florey for the discovery of penicillin and its curative effect in various infectious diseases. The Microbial World: Penicillin and other Antibiotics describes the story of Fleming's discovery of this antibiotic, and the properties that made it such a phenomenal success in fighting bacteria. Florey and Chain shared the prize for producing penicillin on an industrial scale, which made it available for widespread use during World War II. Although health experts soon touted penicillin as a wonder drug, resistant microbes began appearing just four years after drug companies began to mass produce it.

Microbes adapt to survive a variety of pharmaceutical attacks.The first medically significant bacterium to resist penicillin was Staphylococcus aureus. Medical Microbiology describes Staphylococcus as an often harmless passenger in human nasal passages, on mucous membranes, and on the skin. In addition, staph produces toxins that can cause serious infections including pneumonia, meningitis, and toxic shock syndrome. Penicillin disables S. aureus by preventing the cross-linking of peptidoglycan, which is the main polymer of the bacterial cell wall. Unable to maintain structural rigidity, the bacteria lyse and die.

Initially, S. aureus fought back by producing beta-lactamase, an enzyme that hydrolyzes penicillin before it can act. When scientists developed methicillin - another antibiotic in the beta-lactam family of antibiotics and characterized by the same basic ring structure, but stable in the face of the hydrolyzing enzymes of Staphylococcus - bacteria resisted by altering their penicillin-binding proteins. Bacteria often outsmart entire families of drugs.The arms race between Staphylococcus aureus and penicillin is by no means unique.

Bacteria may have an intrinsic resistance to an antibiotic, or they may acquire resistance through several mechanisms. Changes in bacterial chromosomes can produce resistant traits or strengthen existing ones. Also, bacteria can take up DNA from their environment. Stuart Levy's Scientific American article, The Challenge of Antibiotic Resistance, illustrates how bacteria acquire resistance genes: Viruses can deliver DNA picked up from another bacterium, or a bacterium may scavenge bits of DNA from dead bacterial cells nearby. Moreover, plasmids - tiny circular bits of DNA that live in and move between bacteria - often carry resistance genes, and can make a bacterium resistant to more than one antibiotic.

To thwart antibiotics successfully, bacteria must interfere with a drug's mode of action. For example, some bacteria pump out an antibiotic as fast as it comes into a cell, rendering it inactive. Likewise, a change in the target site of the antibiotic or in the composition of the bacterium's outer cell membrane may render a drug inactive, as happened with penicillin. For an antibiotic that interferes with a metabolic pathway, bacteria may substitute an "antidote" that bypasses the step blocked by the drug. Some resistant bacteria even produce enzymes that cleave or alter the drug, making it useless. For animated diagrams of antibiotic-thwarting mechanisms, see Microbial Resistance.

Using antibiotics kills some bacteria, and strengthens others.Once a bacterium acquires resistance, natural selection takes over.

Ironically, the presence or use of an antibiotic can promote resistant bacterial strains. When an antibiotic attacks, susceptible bacteria die. On the other hand, resistant cells survive - especially when too little of the antibiotic is used - and pass their resistance on to future generations. Because their drug-susceptible neighbors are dead, the resistant bacteria multiply with little or no competition.

Once in the gene pool, antibiotic resistance can spread at an alarming rate. According to Protecting the Crown Jewels: A Strategic Plan to Preserve the Effectiveness of Antibiotics at the Web site of the Center for Science in the Public Interest, the incidence of methicillin-resistant staph isolates in U.S. hospitals increased from 2.4 percent in 1975 to 29 percent in 1991. Today, more than 90 percent of staph isolates are resistant to penicillin.

Overuse of antibiotics in agriculture also enhances resistance.Multiple factors contribute to increased antibiotic resistance, and a number of informative and excellent sites provide information on resistance to the public, health care providers, and government agencies. The Alliance for the Prudent Use of Antibiotics, for example, supplies a page called What Is Antibiotic Resistance and Why Is It a Problem?, which warns against demanding antibiotics from your physician and advises consumers who are given antibiotics to take them exactly as prescribed and to complete the full course of treatment. The Centers for Disease Control and Prevention has posted several booklets - including Addressing the Problem of Antimicrobial Resistance - on various facets of antimicrobial resistance and makes recommendations to the scientific and medical community for dealing with this increasingly worrisome problem.

The misuse and overuse of antibiotics in animals and agriculture also increases resistance in bacteria. According to a World Health Organization page called $17 Billion Spent Researching New Drugs in the Past Five Years Could Be Lost Just as Quickly without Global Action, agriculture uses 50 percent of all antibiotic production - some for treating sick animals, but also to promote growth in livestock and poultry. Moreover, drug-resistant microbes developed in animals can be transferred to humans. Consequently, the World Health Organization is launching a comprehensive global strategy to contain the spread of drug resistance. It recommends several actions, including obligatory prescriptions for antibiotic use for disease control in animals and phasing out their use as growth promoters.

Only responsible use of antibiotics protects their effectiveness.More information on antibiotic use in agriculture can be found at the Antibiotic Resistance page from the U.S. Food and Drug Administration. This site provides several links to articles, including Human Health Impact and Regulatory Issues Involving Antimicrobial Resistance in the Food Animal Production Environment and Emerging Antibiotic Resistance: 2000 and Beyond.

At the close of Fleming's Nobel lecture, he issued a caveat: "There may be danger, though, in underdosage. It is not difficult to make microbes resistant to penicillin in the laboratory by exposing them to concentrations not sufficient to kill them, and the same thing may occasionally happen in the human body." From the increasing number of "antibacterial" soaps appearing on supermarket shelves to stories of people stockpiling Cipro in the face of anthrax threats, it appears that Fleming's warning fell on deaf ears. If we don't start using antibiotics responsibly, we may end up without effective ones when we need them most.