New treatment options against gram-negative organisms

Matteo Bassetti Francesca Ginocchio Malgorzata Mikulska - Introduction In recent years, infections caused by multi-drug resistant (MDR) pathogens have become a serious problem, especially in the nosocomial setting. The World Health Organization (WHO) has identified antimicrobial resistance as one of the three most important problems for human health. Some authors have summarized this phenomenon 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-Pacific 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 first Food and Drug Administration (FDA)-approved representative of the glycylcyclines, and doripenem, a new carbapenem, seem the most promising. Since 2001, different agencies and societies have tried to draw attention to the significant 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 Gastroenterological Association, Trust for Americas Health, Society for Healthcare Epidemiology of America, Pediatric Infectious Disease Society, Michigan Antibiotic Resistance Reduction Coalition, National Foundation for Infectious Diseases, and European Society of Clinical Microbiology and Infectious Diseases) [4]. The profile of resistance to currently used antimicrobial agents and the development of new anti-Gram-negative agents, with a particular attention to cephalosporins, lactamase inhibitors and carbapenems will be discussed. Mechanism of resistance to currently used antimicrobial agents in multi-drug resistant gram-negative bacteria -lactamase-mediated resistance is the most important and efficient method of -lactam resistance for Gramnegative bacteria. The origin of -lactamases is presumably ancient and their development evolved to combat natural -lactams. However, resistance has been heavily influenced over the years by the widespread administration of these antibiotics in clinical practice. For example, the rapid increase in resistance to the widelyused ampicillin in the early 1960s turned out to be due to a plasmid-mediated -lactamase, one of the first described in Gram-negative bacteria, known as TEM (the TEM 1 enzyme was originally found in Eschericihia coli isolated from a patient named Temoniera, hence named TEM). The further selection of resistant mutants led to the appearance of extended-spectrum -lactamases (ESBLs) that now compromise the use of even thirdgeneration cephalosporins. In the 1990s, the pharmaceutical industry introduced carbapenems, which are extremely stable to degradation by -lactamases. However, a variety of -lactamases that are capable of hydrolyzing these antibiotics, including imipenemase (IMP), Verona integron-encoded MBL (VIM), K. pneumoniae carbapenemase (KPC) and oxacillinase (OXA) are being increasingly seen in Gram-negative bacterial isolates. Different classifications of -lactamases have been proposed, but the Ambler classification is the most widely used and divides -lactamases into four classes (A, B, C and D) based upon their amino acid sequences (Table 1) [5,6]. Briefly, class A enzymes are plasmidmediated penicillinases, constitutively expressed and susceptible to inhibition by -lactamase inhibitors; representative enzymes include TEM and sulfhydryl reagent variable (SHV) subclasses. Some evolved class A lactamases accept extended-spectrum cephalosporins as substrates and are known as ESBLs, even if there are ESBL enzymes belonging to other classes as well. Class B enzymes are metallo--lactamases (MBL) with broad substrate specificity that includes not only penicillins and cephalosporins, but also carbapenems. Class C enzymes are primarily chromosomally encoded cephalosporinases and are often referred to as AmpC -lactamases resistant to inhibition by -lactamase inhibitors. Finally, class D lactamases have a substrate preference for oxacillin and are therefore called oxacillinases. This class diversity is a crucial aspect for antimicrobial therapy. Recently, a new plasmid MBL, the New Delhi MBL (NDM-1) was identified in K. pneumoniae and E. coli recovered from a Swedish patient who was admitted to hospital in New Delhi, India [7]. Of particular concern is that NDM enzymes are present in E. coli, the most common cause of community-associated urinary tract infections. The NDM-producing bacteria are resistant to many groups of antibiotics, including fluoroquinolones, aminoglycosides, and -lactams (especially carbapenems), and are susceptible only to colistin and tigecycline [7]. Nevertheless, even these two agents might lose their activity. The target of the antimicrobial action of colistin is the bacterial cell membrane and studies on colistin-resistant P. aeruginosa strains have reported alterations at the outer membrane of the cell, leading to resistance [8]. Thus, colistin might not be a long-standing treatment option for MDR Gram-negative bacteria. As far as resistance to tigecycline is concerned, low concentrations attained in the serum are probably the driving force for the development of resistance while on treatment, particularly when the minimum inhibitory concentrations (MICs) of the targeted pathogen exceed the Cmax of the drug, which is almost the rule for all targeted A. baumannii strains [9]. The genetic basis of development of resistance has been investigated with molecular studies and efflux pumps (...truncated)