New Treatment Options Against Gram-Negative Organisms Matteo Bassetti*, Francesca Ginocchio, Malgorzata Mikulska
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Bassetti et al. Critical Care 2011, 15:215 http://ccforum.com/content/15/2/215 REVIEW New treatment options against gram-negative organisms Matteo Bassetti*, Francesca Ginocchio, Malgorzata Mikulska This article is one of eleven reviews selected from the Annual Update in Intensive Care and Emergency Medicine 2011 (Springer Verlag) and co-published as a series in Critical Care. Other articles in the series can be found online at http://ccforum.com/series/annual. Further information about the Annual Update in Intensive Care and Emergency Medicine is available from http://www.springer.com/series/8901 Introduction for Gram-negative pathogens. In fact, in 2004 the In recent years, infections caused by multi-drug resistant Infectious Diseases Society of America (IDSA) issued (MDR) pathogens have become a serious problem, their report, “Bad Bugs, No Drugs: As Antibiotic Dis- especially in the nosocomial setting. Th e World Health covery Stagnates, A Public Health Crisis Brews,” which Organization (WHO) has identifi ed antimicrobial resis- proposed incentives to reinvigorate pharmaceutical tance as one of the three most important problems for investment in antibiotic research and development [2]. In human health. Some authors have summarized this 2007, the IDSA and the FDA repeated their call for an pheno menon with the word ‘ESKAPE’, to include the increase in new antibacterial research to develop next- most frequent MDR microorganisms: Enterococcus generation drugs [3]. Recently, the IDSA supported an faecium, Staphylococcus aureus, Klebsiella pneumoniae, initiative of developing 10 new systemic antibacterial Acinetobacter baumannii, Pseudomonas aeruginosa and drugs through the discovery of new drug classes, as well Enterobacter spp. [1]. Resistance to the current library of as exploring possible new molecules from existing classes antibacterial drugs is a serious problem in all parts of the of antibiotics (the “10 x ‘20” initiative, endorsed by the world including the Asia-Pacifi c region, Latin America, American Academy of Pediatrics, American Gastro- Europe, and North America. entero logical Association, Trust for America’s Health, Numerous classes of antimicrobials are currently Society for Healthcare Epidemiology of America, Pedia- available for physicians to use in the treatment of patient tric Infectious Disease Society, Michigan Antibiotic with infections; however, the pace of antibiotic drug Resis tance Reduction Coalition, National Foundation for development has slowed during the last decade (Fig. 1). Infectious Diseases, and European Society of Clinical In particular, the pharmaceutical pipeline of antibiotics Microbiology and Infectious Diseases) [4]. active against MDR Gram-negative bacteria is very Th e profi le of resistance to currently used antimicrobial limited. New antibiotics that have been discovered and agents and the development of new anti-Gram-negative introduced into clinical practice in the last few years are agents, with a particular attention to cephalosporins, β- active mostly against Gram-positive organisms, whereas lactamase inhibitors and carbapenems will be discussed. when targeting resistant Gram-negative bacteria, clini- cians are forced to rediscover old drugs, such as poly- Mechanism of resistance to currently used mixins and fosfomycin. Among new antibacterials active antimicrobial agents in multi-drug resistant against Gram-negative microorganisms that are already gram-negative bacteria on the market, tigecycline, the fi rst Food and Drug β-lactamase-mediated resistance is the most important Administration (FDA)-approved representative of the and effi cient method of β-lactam resistance for Gram- glycylcyclines, and doripenem, a new carbapenem, seem negative bacteria. Th e origin of β-lactamases is presu- the most promising. mably ancient and their development evolved to combat Since 2001, diff erent agencies and societies have tried natural β-lactams. However, resistance has been heavily to draw attention to the signifi cant lack of new antibiotics infl uenced over the years by the widespread adminis- tration of these antibiotics in clinical practice. For *Correspondence: [email protected] example, the rapid increase in resistance to the widely- Clinica Malattie Infettive, A.O.U. San Martino, L.go R. Benzi 10, 16132 Genoa, Italy used ampicillin in the early 1960s turned out to be due to © 2011 Springer-Verlag Berlin Heidelberg. This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, specifi cally the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfi lm or in any other way, and storage in data banks. Duplication of this publication or parts thereof is permitted only under the provisions of the German Copyright Law of September 9, 1965, in its current version, and permission for use must always be obtained from Springer-Verlag. Violations are liable for prosecution under the German Copyright Law. Bassetti et al. Critical Care 2011, 15:215 Page 2 of 9 http://ccforum.com/content/15/2/215 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. Th e NDM-producing bacteria are resistant to many groups of antibiotics, including fl uoroquinolones, aminoglycosides, and β-lactams (especially carbapenems), and are suscep- tible only to colistin and tigecycline [7]. Nevertheless, even these two agents might lose their activity. Th e 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 Figure1. New antibacterial agents approved in the United outer membrane of the cell, leading to resistance [8]. States, 1983–2009. From [3] with permission. Th us, colistin might not be a long-standing treatment option for MDR Gram-negative bacteria. As far as resistance to tigecycline is concerned, low concentrations a plasmid-mediated β-lactamase, one of the fi rst attained in the serum are probably the driving force for described in Gram-negative bacteria, known as TEM (the the development of resistance while on treatment, TEM 1 enzyme was originally found in Eschericihia coli particularly when the minimum inhibitory concentra- isolated from a patient named Temoniera, hence named tions (MICs) of the targeted pathogen exceed the Cmax TEM). Th e further selection of resistant mutants led to of the drug, which is almost the rule for all targeted A. the appearance of extended-spectrum β-lactamases baumannii strains [9]. Th e genetic basis of development (ESBLs) that now compromise the use of even third- of resistance has been investigated with molecular studies generation cephalosporins. In the 1990s, the pharma- and effl ux pumps seem to be the most important ceutical industry introduced carbapenems, which are mechanism of decreased susceptibility. Various effl ux extremely stable to degradation by β-lactamases. How- pumps have been reported in E. coli, E. cloacae, K. ever, a variety of β-lactamases that are capable of hydro- pneumoniae and A. calcoaceticus-A. baumannii [10]. lyzing these antibiotics, including imipenemase (IMP), Verona integron-encoded MBL (VIM), K. pneumoniae Gram-negative resistant bacteria and drug carbapenemase (KPC) and oxacillinase (OXA) are being development needs increasingly seen in Gram-negative bacterial isolates. Given the continuous increase in antibiotic resistance, the Diff erent classifi cations of β-lactamases have been IDSA’s Antimicrobial Availability Task Force identi fi ed proposed, but the Ambler classifi cation is the most development needs for the ESKAPE pathogens, includ ing widely used and divides β-lactamases into four classes (A, Gram-negatives such as E. coli, Klebsiella spp., Entero- B, C and D) based upon their amino acid sequences bacter spp., P. aeruginosa and Acinetobacter spp. [1,11]. (Table 1) [5,6]. Briefl y, class A enzymes are plasmid- In Enterobacteriaceae, the main resistance problems mediated penicillinases, constitutively expressed and sus- stem from production of ESBL, inducible chromosomal ceptible to inhibition by β-lactamase inhibitors; repre- cephalosporinases and carbapenemases, including K. sen tative enzymes include TEM and sulfhydryl reagent pneumoniae carbapenemase (KPC)-hydrolyzing β-lacta- variable (SHV) subclasses. Some evolved class A β- mases [12]. Infections due to ESBL-producing E. coli and lactamases accept extended-spectrum cephalosporins as Klebsiella spp. continue to increase in frequency and substrates and are known as ESBLs, even if there are severity. In an interesting meta-analysis of 16 studies, ESBL enzymes belonging to other classes as well. Class B bacteremias caused by ESBL-producing pathogens were enzymes are metallo-β-lactamases (MBL) with broad signifi cantly associated with delayed initiation of eff ective substrate specifi city that includes not only penicillins and therapy and increased crude mortality [13]. Additionally, cephalosporins, but also carbapenems. Class C enzymes Enterobacter causes an increasing number of health care- are primarily chromosomally encoded cephalosporinases associated infections and is increasingly resistant to and are often referred to as AmpC β-lactamases resistant multiple antibacterials [12]. Enterobacter infections, to inhibition by β-lactamase inhibitors. Finally, class D β- especially bloodstream infections, are associated with lactamases have a substrate preference for