New treatment options against gram-negative organisms

In recent years, infections caused by multi-drug resistant (MDR) pathogens have become a serious problem, especially in the nosocomial setting. Th e World Health Organization (WHO) has identifi ed antimicrobial resistance as one of the three most important problems for human health. Some authors have summarized this pheno menon with the word ‘ESKAPE’, to include the most frequent MDR microorganisms: Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter spp. [1]. Resistance to the current library of antibacterial drugs is a serious problem in all parts of the world including the Asia-Pacifi c region, Latin America, Europe, and North America. Numerous classes of antimicrobials are currently available for physicians to use in the treatment of patient with infections; however, the pace of antibiotic drug development has slowed during the last decade (Fig. 1). In particular, the pharmaceutical pipeline of antibiotics active against MDR Gram-negative bacteria is very limited. New antibiotics that have been discovered and introduced into clinical practice in the last few years are active mostly against Gram-positive organisms, whereas when targeting resistant Gram-negative bacteria, clinicians are forced to rediscover old drugs, such as polymixins and fosfomycin. Among new antibacterials active against Gram-negative microorganisms that are already on the market, tigecycline, the fi rst Food and Drug Administration (FDA)-approved representative of the glycylcyclines, and doripenem, a new carbapenem, seem the most promising. Since 2001, diff erent agencies and societies have tried to draw attention to the signifi cant lack of new antibiotics for Gram-negative pathogens. In fact, in 2004 the Infectious Diseases Society of America (IDSA) issued their report, “Bad Bugs, No Drugs: As Antibiotic Discovery Stagnates, A Public Health Crisis Brews,” which proposed incentives to reinvigorate pharmaceutical investment in antibiotic research and development [2]. In 2007, the IDSA and the FDA repeated their call for an increase in new antibacterial research to develop nextgeneration drugs [3]. Recently, the IDSA supported an initiative of developing 10 new systemic antibacterial drugs through the discovery of new drug classes, as well as exploring possible new molecules from existing classes of antibiotics (the “10 x ‘20” initiative, endorsed by the American Academy of Pediatrics, American Gastroentero logical Association, Trust for America’s Health, Society for Healthcare Epidemiology of America, Pediatric Infectious Disease Society, Michigan Antibiotic Resis tance Reduction Coalition, National Foundation for Infectious Diseases, and European Society of Clinical Microbiology and Infectious Diseases) [4]. Th e profi le of resistance to currently used antimicrobial agents and the development of new anti-Gram-negative agents, with a particular attention to cephalosporins, βlactamase inhibitors and carbapenems will be discussed.