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Discovery and development of new antibiotics: the problem of antibiotic resistance

Real clinical needs for new antimicrobial antibiotics derive from the emergence and dissemination of new opportunistic pathogens, especially in a growing immune system-debilitated host population. The significant health problems that occur as a result of infections with these rare or opportunistic pathogens is an outgrowth of the AIDS epidemic as well as the increasing prevalence of aggressive cancer chemotherapy and organ transplantation. Therapeutic needs can often be met by optimizing the use of existing chemotherapeutic agents. However, commonly prescribed antibiotics may not sufficiently cover these organisms, and the rapid spread or development of antibiotic resistance may compromise standard empiric treatment. Indeed, the greatest threat to successful antibiotic coverage, and hence the driving force behind the search for new therapies, is the evolution and spread of antibiotic resistance. Resistance of common or resurgent pathogens to standard antibiotic therapies is a significant nosocomial problem and is of increasing importance in communityacquired infections as well. In the hospital setting, especially tertiary-care facilities (40), the incidence of drug-resistant gram-positive infections is increasing-notably among Staphylococcus aureus, coagulase-negative staphylococci, corynebacteria, and enterococci-while drug resistance in gram-negative organisms, including Pseudomonas, Serratia, andAcinetobacter species, continues to pose problems (20). The recent appearance of virulent strains of Mycobactenum tuberculosis that are resistant to multiple antibiotics in the AIDS, illegal drug addict, and prison populations has caused great alarm, posing a threat to the wider community and a potential resurgence of the disease (1). Empiric therapy favors the use and hence the development of broad-spectrum agents and combinations (7), even though the underlying need may be for treatment of specific problem pathogens, such as Pseudomonas species or methicillin-resistant staphylococci. While future technological refinements may bring rapid diagnostic methods and lead to effective dosing with narrow-spectrum agents, the current strategy is to develop antibiotics with good pharmacological profiles and (relatively) broad spectra of activity, including activity against the problem pathogens. The effective spectrum of an antibiotic, for empirical dosing, is determined by the MIC for 90% of strains tested, which, when it is based on