Chapter 1: Introduction
1.5 Carbapenem Resistance
1.5.4 Global Distribution of Carbapenemases of
variants of this gene have been identified. The fifth subgroup is the OXA-58 and was identified in a multidrug resistant A. baumannii clinical isolate in France in 2003 (Poirel et al., 2005), and three variants of this gene has been distinguished. The sixth subgroup OXA-134a was identified from A. lwoffii (Figueiredo et al., 2010), and six variants of this gene have been identified. The seventh subgroup, OXA-143, was identified in an A. baumannii strain in Brazil in 2004 (Higgins et al., 2009) and four variants have been identified. Recent studies on Acinetobacter species have helped to identify new enzyme subgroups (Evans and Amyes, 2014). These new enzymes include OXA-211 from Acinetobacter johnsonii (Figueiredo et al., 2012), OXA-213 from Acinetobacter calcoaceticus (Figueiredo et al., 2012), OXA-214 from Acinetobacter hemolyticus (Figueiredo et al., 2012), OXA-299 from Acinetobacter bereziniae (Bonnin et al., 2012), and OXA -235 from Acinetobacter baumannii (Higgins et al., 2013).
Mediterranean to countries such as Greece where the situation currently is endemic (Giakkoupi et al., 2011). In the USA it is still the most common carbapenemase, the only one with endemic appearance.
Figure 3: The global distribution of the most common carbapenemases (Logan and Weinstein, 2017)
By now KPC producing strains are wide-spread in healthcare facilities in Italy (Nordmann et al., 2011). A rapid increase in these cases were also described by France and Spain (Carbonne et al., 2010; Gomez-Gil et al., 2010). In most of the cases in France the patients were transferred from countries where KPC enzymes were endemic, such as Israel, Greece, USA or Italy (Cuzon et al., 2012). Europe is the most
affected continent when it comes to KPC-2 (Nordmann et al., 2009). Another affected Mediterranean country is Croatia (Bedenic et al., 2012). KPC producers have also been isolated from an E. coli isolate in Algeria (Djahmi et al., 2014).
While the blaKPC gene can be present in sporadic strains, often, particularly in outbreak situations, it is associated with globally-distributed clones, such as ST258 and CC258 in K pneumoniae.
The first metallo beta-lactamase identified was IMP-1 which was identified in S. marcescens from Japan, in 1991 (Ito et al., 1995). After this finding, various MBLs, mostly VIM and IMP enzymes, had been observed worldwide (Walsh et al., 2005;
Vatopoulos, 2008; Nordmann et al., 2011). A particularly heavily hit region was Italy, with sporadic isolates of VIM-4 producing E. cloaceae and K. pneumoniae (Luzzaro et al., 2004). Since then many cases of VIM-1 have been reported from various regions around this country (Aschbacher et al., 2008). Endemic cases of IMP and VIM producing K. pneumoniae have been reported in Greece (Walsh et al., 2005). Similarly, cases have now been reported from France (Poirel et al., 2011), Egypt (Giani et al., 2012), Algeria (Robin et al., 2010), Spain (Oteo et al., 2013), Morocco (Barguigua et al., 2013), and Tunisia (Ktari et al., 2006).
The MBL scenario has fundamentally changed by the discovery of a new type of enzyme, the New Delhi Metallo beta-lactamase (NDM) in a K. pneumoniae urinary tract isolate from a Swedish patient of Indian origin, who received treatment in his native country (Yong et al., 2009). Since then NDM, and particularly its allele NDM- 1, has spread globally (Nordmann et al., 2011). For a while, the American continent has been spared, but by now cases started appearing there too (Pasteran et al., 2012).
For NDM-1, the Indian subcontinent is considered to be the reservoir but secondary reservoir regions, e.g. the Balkan countries (Livermore et al., 2011) and the Middle
East (Poirel et al., 2011) have emerged since. Minor variants of NDM-1 have now been identified in Enterobacteriaceae (NDM- 2 to NDM- 6). Very recently NDM-7 was identified in E. coli in France (Cuzon et al., 2013). These enzymes are encoded on highly transmissible plasmids that spread rapidly in between species and the spread of NDM does not depend on clonal expansion (Kumarasamy et al., 2010). Nevertheless, not uncommonly, it can also associate with such well-known K. pneumoniae clones as ST101 or ST11 (Logan and Weinstein, 2017).
NDM-1 has also been identified in E. coli ST131, which causes extraintestinal community infections (Nicolas-Chanoine et al., 2008). NDM-1 producing Enterobacteriaceae strains have been reported from many Mediterranean countries such as Italy (Giani et al., 2013), France (Birgy et al., 2011), Morocco (Barguigua et al., 2013), Lebanon (Baroud et al., 2012), Turkey (Poirel et al., 2012), Spain (Oteo et al., 2013) and Tunisia (Ben Nasr et al., 2013). Very recently NDM-5 was identified in Algeria in an E. coli isolate. NDM-1 in a K. pneumoniae isolate was identified from a patient transferred from Libya to Tunisia (Ben Nasr et al., 2013), indicating the emergence of this enzyme resistance in the Mediterranean countries. Finally, an NDM producing K. pneumoniae was recently reported in Greece (Giakkoupi et al., 2013).
OXA-48 was first identified in K. pneumoniae in Turkey in 2001 (Poirel et al., 2004). Since then, OXA-48 producing strains have been reported to cause nosocomial outbreaks in many parts of the Mediterranean such as Egypt (Poirel et al., 2013), France (Potron et al., 2013), Greece (Voulgari et al., 2013), Croatia (Vranic-Ladavac et al., 2014), Italy (Giani et al., 2012), Israel (Adler et al., 2011), Libya (Djahmi et al., 2014), Slovenia (Pirs et al., 2011), Lebanon (Birgy et al., 2011), Tunisia (Ktari et al., 2011), Turkey (Carrer et al., 2010) and Spain (Oteo et al., 2013). This enzyme has disseminated into various Enterobacteriaceae species (Nordmann et al., 2011).
Although by now present in all continents, countries with endemic OXA-48 producers mostly include those of the Middle East and North Africa (Poirel et al., 2012), i.e. the Mediterranean region, in general. Different hospitals in Morocco have reported many cases of OXA-48 producing Enterobacteriaceae (Hays et al., 2012). Very recently blaOXA-48 gene in a K. pneumoniae isolate was reported in Algeria (Djahmi et al., 2014).
1.6 Antibotics Frequently used in Combination with, or as an Alternatives to Carbapenems
As said before, carbapenems, on one hand, are often combined with drugs such as aminoglycosides, tigecycline or colistin, or these drugs, particularly the latter two, are the ones considered as reserve agents, in case of resistance to carbapenems.
Therefore, assessing susceptibilities against them provides crucial information when testing CRE and we will briefly describe them.