Starting with penicillin, the 'wonder drugs' did a brilliant job of combating bacterial infections and saving lives. But they also created a dangerous threat--new strains of bacteria that resist them.

EVERY SCHOOLCHILD MUST BE FAMILIAR with the story of Alexander Fleming and the discovery of a bacteria-killing mold he called penicillin. What they probably don't know is that having found the mold in 1928, he didn't do anything much with it.

It was not until 1938 that two Oxford University scientists, Howard Florey and Ernst Chain, went back to Fleming's mold, eventually found a way to produce penicillin and, by 1942, showed it could be used to treat infections. (For their work, the three shared the 1945 Nobel Prize in Physiology or Medicine.) Once purified and available in usable quantities, penicillin was an instant success. It became an important weapon for the Allies in the last years of World War II, saving thousands of soldiers who otherwise would have died from infected wounds.

After the war, penicillin and the other new "wonder drugs" that were being developed were at last available to use against such life-threatening diseases as syphilis, pneumonia, tuberculosis and bacterial meningitis. "Antibiotics gave physicians the opportunity to intervene in these infectious diseases for the first time," says Dr. Mitchell Cohen, head of the bacterial-disease division at the Centers for Disease Control and Prevention. "If you had a sick patient who had a 50 percent chance of dying, you could give a drug and drop the death rate to less than 1 percent. This was a phenomenal advance.

It was an advance that transformed medicine. The idea of a drug that cures a specific illness is a peculiarly modern one. Well into the 19th century, most medications were prescribed as "tonics" for the patient's general condition. The noted bacteriologist Paul Ehrlich coined the term "magic bullet" for a drug that was targeted at a certain disease-causing microbe and applied it to his own concoction, Salvarsan, which was introduced in 1910 as a treatment for syphilis. Sulfa drugs to prevent sepsis in wounds and to treat certain infectious diseases followed in the 1930s. Soon the public began to expect the same kind of "cure for all medical problems. Cancer chemotherapy, antiviral agents and new drugs to control blood pressure, serum cholesterol, gastric secretions and the symptoms of schizophrenia were just a few of the fruits of the revolution in pharmacology that began with penicillin.

"Antibiotic," a term coined by soil microbiologist Selman Waksman of Rutgers University, discoverer of streptomycin, may not have been the best choice of name. "Antibacterial" might have been better. A literal translation of antibiotic suggests the drugs are effective against all kinds of living organisms, with the result that many people look to antibiotics as a miracle cure for all ailments. But antibiotics have no effect on viruses and other disease-causing organisms. Many viruses can be controlled with good vaccines--a noted exception is HIV, which causes AIDS--but vaccines are generally not effective against bacterial infections, such as staphylococci and streptococcus.

And antibiotics have proved a double-edged sword. Fleming himself anticipated that bacteria would figure out ways around the new drugs. Within four years of the first use of penicillin, some types of staph infections were already showing signs of immunity to the drug.

Staphylococcus aureus is an especially nasty bug and one of the most common causes of infection in the world. It offers a particularly chilling example of the emergence and the persistent reemergence of resistant strains. Through history, people with staph infections often died, but, says Dr. Anthony Fauci, head of the National Institute on Allergy and Infectious Diseases, "that never happens in modern times." Staphylococcus was initially very sensitive to penicillin. When penicillin resistance developed, physicians turned to the next line of defense, which was another antibiotic called methicillin. That worked until the '70s. By then medicine had an ace in the hole in the form of vancomycin. Now cases of partial resistance to vancomycin are being reported, and it may not be long before strains with full resistance emerge. "If resistance does spread and we don't have a good drug to replace vancomycin we're in trouble," warns Fauci. "This is a serious infection."

If penicillin came from a chance discovery in a petri dish, the drugs that followed were the result era more systematic hunt. Waksman, searching soil samples for other antibiotics, selected 10 promising microorganisms from more than 10,000 cultures. Among them was streptomycin, isolated in 1943, which turned out to kill the bacteria that caused common urinary tract infections and others that caused meningitis. It also was the first drug of any kind that helped people suffering from one of mankind's greatest scourges, tuberculosis.

Yet there were problems with streptomycin. It had side effects not seen with penicillin. The doses needed to cure tuberculosis could cause kidney damage and temporary deafness. And bacteria quickly became resistant to the drug. Scientists immediately started looking for other drugs with the same effectiveness but without those shortcomings. Over the years they came up with a string of alternatives, including neomycin, kanamycin, gentamicin and tobramycin.

Other scientists began looking through soil samples acquired from all corners of the world. In 1947 Yale University micro-biologist Paul Burkholder, working with the Parke-Davis Co., discovered a substance that seemed to kill a wide variety of bacteria; it had turned up in a sample scooped from a field near Caracas, Venezuela. The compound, named Chloromycetin, or chloramphenicol, was the first of the broad-spectrum antibiotics to work against previously untreatable diseases such as typhoid, typhus and Rocky Mountain spotted fever.

By the '80s, with so many antibiotics already on the market, drugmakers had lost interest in developing new ones. The threat from resistance brought some firms back to antibiotic research, trying to foil the strategies bacteria employ to become resistant. But doctors worry that their arsenal of pharmaceutical weapons against drug-resistant bacteria is becoming seriously depleted. "More of the large companies have gotten back into antibiotic research because they've seen the need," says Dr. Stuart Levy of Tuffs School of Medicine, author of "The Antibiotic Paradox," "but we will still not have the new drugs by 2000."

In the meantime, Cohen argues for a return to tried and true public-health measures, including more frequent handwashing by health-care and food workers, isolation of patients with resistant infections and improved sewage treatment and water purity, especially in developing countries. In the jet age, it doesn't matter where resistant strains evolve. "If we can prevent people from getting infected, we won't need to treat," he points out. If that doesn't work, mankind could be in for a few rough years as scientists try once more to catch up with an extremely formidable foe.

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