Abstract
Carbapenem resistance in gram-negative bacteria has caused a global epidemic that continues to grow. Although carbapenemase-producing Enterobacteriaceae have received the most attention ...because resistance was first reported in these pathogens in the early 1990s, there is increased awareness of the impact of carbapenem-resistant nonfermenting gram-negative bacteria, such as Acinetobacter baumannii, Pseudomonas aeruginosa, and Stenotrophomonas maltophilia. Moreover, evaluating the problem of carbapenem resistance requires the consideration of both carbapenemase-producing bacteria as well as bacteria with other carbapenem resistance mechanisms. Advances in rapid diagnostic tests to improve the detection of carbapenem resistance and the use of large, population-based datasets to capture a greater proportion of carbapenem-resistant organisms can help us gain a better understanding of this urgent threat and enable physicians to select the most appropriate antibiotics.
SUMMARYPolymyxins are well-established antibiotics that have recently regained significant interest as a consequence of the increasing incidence of infections due to multidrug-resistant Gram-negative ...bacteria. Colistin and polymyxin B are being seriously reconsidered as last-resort antibiotics in many areas where multidrug resistance is observed in clinical medicine. In parallel, the heavy use of polymyxins in veterinary medicine is currently being reconsidered due to increased reports of polymyxin-resistant bacteria. Susceptibility testing is challenging with polymyxins, and currently available techniques are presented here. Genotypic and phenotypic methods that provide relevant information for diagnostic laboratories are presented. This review also presents recent works in relation to recently identified mechanisms of polymyxin resistance, including chromosomally encoded resistance traits as well as the recently identified plasmid-encoded polymyxin resistance determinant MCR-1. Epidemiological features summarizing the current knowledge in that field are presented.
Highlights • Multidrug resistance is increasingly reported among Acinetobacter baumannii and Pseudomonas aeruginosa clinical isolates. • Extended-spectrum β-lactamases (ESBLs) and carbapenemases are ...the most threatening resistance mechanisms. • Pandrug resistance to aminoglycosides is now increasingly reported owing to the acquisition of 16S rRNA methylases. • Resistances to tigecycline and colistin are on the rise in A. baumannii. • Combination of all these resistance mechanisms may lead to pandrug resistance in A. baumannii and P. aeruginosa.
Carbapenemases increasingly have been reported in Enterobacteriaceae in the past 10 years. Klebsiella pneumoniae carbapenemases have been reported in the United States and then worldwide, with a ...marked endemicity at least in the United States and Greece. Metallo-enzymes (Verona integron-encoded metallo-β-lactamase, IMP) also have been reported worldwide, with a higher prevalence in southern Europe and Asia. Carbapenemases of the oxacillinase-48 type have been identified mostly in Mediterranean and European countries and in India. Recent identification of New Delhi metallo-β-lactamase-1 producers, originally in the United Kingdom, India, and Pakistan and now worldwide, is worrisome. Detection of infected patients and carriers with carbapenemase producers is necessary for prevention of their spread. Identification of the carbapenemase genes relies mostly on molecular techniques, whereas detection of carriers is possible by using screening culture media. This strategy may help prevent development of nosocomial outbreaks caused by carbapenemase producers, particularly K. pneumoniae.
To rapidly identify carbapenemase producers in Enterobacteriaceae, we developed the Carba NP test. The test uses isolated bacterial colonies and is based on in vitro hydrolysis of a carbapenem, ...imipenem. It was 100% sensitive and specific compared with molecular-based techniques. This rapid (<2 hours), inexpensive technique may be implemented in any laboratory.
Performances of the Rapidec Carba NP test (bioMérieux) were evaluated for detection of all types of carbapenemases in Enterobacteriaceae, Acinetobacter baumannii, and Pseudomonas aeruginosa. In less ...than 2 h after sample preparation, it showed a sensitivity and specificity of 96%. This ready-to-use test is well adapted to the daily need for detection of carbapenemase producers in any laboratory worldwide.
Summary From early this decade, Enterobacteriaceae that produce Klebsiella pneumoniae carbapenemases (KPC) were reported in the USA and subsequently worldwide. These KPC-producing bacteria are ...predominantly involved in nosocomial and systemic infections; although they are mostly Enterobacteriaceae, they can also be, rarely, Pseudomonas aeruginosa isolates. KPC β lactamases (KPC-1 to KPC-7) confer decreased susceptibility or resistance to virtually all β lactams. Carbapenems (imipenem, meropenem, and ertapenem) may thus become inefficient for treating enterobacterial infections with KPC-producing bacteria, which are, in addition, resistant to many other non-β-lactam molecules, leaving few available therapeutic options. Detection of KPC-producing bacteria may be difficult based on routine antibiotic susceptibility testing. It is therefore crucial to implement efficient infection control measures to limit the spread of these pathogens.
For identification of polymyxin resistance in Enterobacteriaceae, we developed a rapid test that detects glucose metabolization associated with bacterial growth in the presence of a defined ...concentration of colistin or polymyxin B. Formation of acid metabolites is evidenced by a color change (orange to yellow) of a pH indicator (red phenol). To evaluate the test, we used bacterial colonies of 135 isolates expressing various mechanisms of colistin resistance (intrinsic, chromosomally encoded, and plasmid-mediated MCR-1) and 65 colistin-susceptible isolates. Sensitivity and specificity were 99.3% and 95.4%, respectively, compared with the standard broth microdilution method. This new test is inexpensive, easy to perform, sensitive, specific, and can be completed in <2 hours. It could be useful in countries facing endemic spread of carbapenemase producers and for which polymyxins are last-resort drugs.
The management of infections due to Klebsiella pneumoniae has been complicated by the emergence of antimicrobial resistance, especially to carbapenems. Resistance to carbapenems in K. pneumoniae ...involves multiple mechanisms, including the production of carbapenemases (e.g., KPC, NDM, VIM, OXA-48-like), as well as alterations in outer membrane permeability mediated by the loss of porins and the upregulation of efflux systems. The latter two mechanisms are often combined with high levels of other types of β-lactamases (e.g., AmpC). K. pneumoniae sequence type 258 (ST258) emerged during the early to mid-2000s as an important human pathogen and has spread extensively throughout the world. ST258 comprises two distinct lineages, namely, clades I and II, and it seems that ST258 is a hybrid clone that was created by a large recombination event between ST11 and ST442. Incompatibility group F plasmids with blaKPC have contributed significantly to the success of ST258. The optimal treatment of infections due to carbapenemase-producing K. pneumoniae remains unknown. Some newer agents show promise for treating infections due to KPC producers; however, effective options for the treatment of NDM producers remain elusive.
The emergence of one of the most recently described carbapenemases, namely, the New Delhi metallo-lactamase (NDM-1), constitutes a critical and growingly important medical issue. This resistance ...trait compromises the efficacy of almost all lactams (except aztreonam), including the last resort carbapenems. Therapeutical options may remain limited mostly to colistin, tigecycline, and fosfomycin. The main known reservoir of NDM producers is the Indian subcontinent whereas a secondary reservoir seems to have established the Balkans regions and the Middle East. Although the spread of b l a NDM -like genes (several variants) is derived mostly by conjugative plasmids in Enterobacteriaceae, this carbapenemase has also been identified in P. aeruginosa and Acinetobacter spp. Acinetobacter sp. may play a pivotal role for spreading b l a NDM genes for its natural reservoir to Enterobacteriaceae. Rapid diagnostic techniques (Carba NP test) and screening of carriers are the cornerstone to try to contain this outbreak which threatens the efficacy of the modern medicine.
PDF
