Abstract
The emergence of carbapenem-resistant Gram-negative pathogens poses a serious threat to public health worldwide. In particular, the increasing prevalence of carbapenem-resistant Klebsiella pneumoniae is a major source of concern. K. pneumoniae carbapenemases (KPCs) and carbapenemases of the oxacillinase-48 (OXA-48) type have been reported worldwide. New Delhi metallo-β-lactamase (NDM) carbapenemases were originally identified in Sweden in 2008 and have spread worldwide rapidly. In this review, we summarize the epidemiology of K. pneumoniae producing three carbapenemases (KPCs, NDMs, and OXA-48-like). Although the prevalence of each resistant strain varies geographically, K. pneumoniaeproducing KPCs, NDMs, and OXA-48-like carbapenemases have become rapidly disseminated. In addition, we used recently published molecular and genetic studies to analyze the mechanisms by which these three carbapenemases, and major K. pneumoniae clones, such as ST258 and ST11, have become globally prevalent. Because carbapenemase-producing K. pneumoniae are often resistant to most β-lactam antibiotics and many other non-β-lactam molecules, the therapeutic options available to treat infection with these strains are limited to colistin, polymyxin B, fosfomycin, tigecycline, and selected aminoglycosides. Although, combination therapy has been recommended for the treatment of severe carbapenemase-producing K. pneumoniae infections, the clinical evidence for this strategy is currently limited, and more accurate randomized controlled trials will be required to establish the most effective treatment regimen. Moreover, because rapid and accurate identification of the carbapenemase type found in K. pneumoniaemay be difficult to achieve through phenotypic antibiotic susceptibility tests, novel molecular detection techniques are currently being developed.
Introduction
The increasing prevalence of antibiotic resistance and the lack of new antibiotic drug development has gradually reduced the treatment options for bacterial infections (Lee et al., 2013a; Nathan and Cars, 2014). In 2013, the Centers for Disease Control and Prevention (CDC) named three microorganisms that pose an urgent threat to public health: carbapenem-resistant (CR) Enterobacteriaceae (CRE), drug-resistant Neisseria gonorrhoeae, and Clostridium difficile (Zowawi et al., 2015). Carbapenems (imipenem, meropenem, biapenem, ertapenem, and doripenem) are antibiotics used for the treatment of severe infections caused by multi-resistant Enterobacteriaceae, such as Klebsiella pneumoniae and Escherichia coli (Nordmann et al., 2009). However, over the past 10 years, CRE have increasingly been reported worldwide (Nordmann et al., 2011a). In particular, K. pneumoniae have acquired carbapenemases, which are enzymes capable of breaking down most β-lactams including carbapenems, and thus conferring resistance to these drugs (Jeon et al., 2015). High mortality rates have been reported in patients with bloodstream infections caused by CR K. pneumoniae (Munoz-Price et al., 2013). Carbapenemases can be divided according to their dependency on divalent cations for enzyme activation into metallo-carbapenemases (zinc-dependent class B) and non-metallo-carbapenemases (zinc-independent classes A, C, and D; Jeon et al., 2015). The class A carbapenemases, such as the K. pneumoniae carbapenemase (KPC) enzymes, have been identified worldwide in K. pneumoniae (Tangden and Giske, 2015). Various class B and D carbapenemases have also been detected in hospital-acquired multi-resistant K. pneumoniae(Nordmann et al., 2011a), whereas class C carbapenemases have rarely been reported. In this review, we summarize the epidemiology of the major four classes of carbapenemases and discuss their molecular genetics, methods used for their detection, and the therapeutic options available for their treatment.
Fuente: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4904035/