Prescription for Mutant Prevention.

In the battle against drug-resistant microbes, it might be necessary to change the rules governing what constitutes an effective antibiotic. The standard, says Paul Tulkens, a professor of pharmacology at Catholic University in Louvain, Belgium, is for manufacturers to create antibiotics that achieve a minimum inhibitory concentration (MIC), the amount of antibiotic required to inhibit growth of--but not necessarily kill--a given bacterium in vitro. Tulkens claims a better system would target a so-called mutant prevention concentration (MPC), the amount required to prevent emergence of mutant, resistant strains in vitro by actually killing the bacterium.

This concept was first developed by scientists at the Public Health Research Institute in New York. In a paper published in the September 2000 issue of Antimicrobial Agents and Chemotherapy, they wrote, "[W]e have defined a drug concentration threshold above which bacterial cells require the presence of two or more resistance mutations for growth. ... [A]dministration of antibiotic above the [MPC] threshold ... should severely restrict selection of resistant mutants."

"Inhibition doesn't go far enough," Tulkens argued during a presentation at the September 2000 Interscience Conference on Antimicrobial Agents and Chemotherapy. "You want to go beyond inhibition to kill the microbes." Tulkens says that newer antibiotics such as moxifioxacin and gatifioxacin are not only capable of achieving acceptable MIC at low doses, but also go on to kill the bugs, preventing the bacteria from developing defenses against the new compounds; in effect, they achieve MPC.

The need for drugs that combat resistance is urgent, Tulkens says, especially in a world in which resistance to beta-lactam antibiotics (the penicillin family) is as high as 80% among some pneumonia-causing microbes. For example, Tulkens says, Streptococcus pneumoniae resistance or decreased sensitivity to beta-lactams can be as high as 40% in some regions of North America, 60% in southern Europe, 36% in Latin America, and 67% in the Asia-Pacific region. Resistant strains of Moraxella catarrhalis are found over 80% of the time in North America and 50-80% of the time in Latin America. And Haemophilus influenzae resistance is found in up to 30% of strains in Europe.

Exactly how well the MPC concept will be accepted will take time to see, says Donald Low, head of the Department of Microbiology at the University of Toronto. In order for regulatory agencies such as the U.S. Food and Drug Administration (FDA) to accept MPC, he says, clinical trials must show that such drugs correlate not only with clinical efficacy but with the prevention of resistance.

But the concept of MPC has not penetrated the FDA. Mark Goldberger, director of the FDA Division of Special Pathogen and Immunologic Drug Products, says, "I don't believe that there has been any discussion of [MPC as a] major criterion for approval." Goldberger notes, however, that drug submissions to the FDA do contain microbiologic data, which generally includes information on the drug's ability to generate resistant organisms. "Although a favorable result in such testing is encouraging," he says, "it must be viewed in the context of overall efficacy and safety."