the (Korzeniewska, E. and M. Harnisz, 2013; Muller, A.,

the rate has increased every year, with over 9500 new cases during 2015( www.folkhalsomyndigheten.se/amnesomraden/statistikochundersokningar/sjukdomsstatistik /extended-spectrum-beta-lactamase-esbl/).

2.8.5 Factors important for the transmission of resistance

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Dissemination of EPE within a country and worldwide is multifactorial and includes humans, animals, and environmental factors. Dissemination between household contacts has been shown in several studies (Valverde, A., et al., 2008; Lo, W.U., et al., 2010) . In a Norwegian study on infants colonized by EPE during an outbreak at the neonatal intensive care unit, transmission within households was observed in 9/28, 32% (Rocha-Gracia, R.C., et al., 2015). EPE has been detected as well in pets (Lohr, I.H., et al., 2013;  Sallem, R.B., et al., 2013), poultry and cattle (Horton, R.A., et al., 2011) as in wild animals, for example, birds (Alcala, L., et al., 2015). In countries with high prevalence of intestinal EPE-colonization, dissemination occurs easily in the community. Except for the intestine in mammals and birds, several other reservoirs for EPE exist, for example, sewage water and the surface of fruits and vegetables (Korzeniewska, E. and M. Harnisz, 2013; Muller, A., R. Stephan, and M. Nuesch-Inderbinen 2015). ESBLs and the carbapenemase gene New Delhi Metallo-?-lactamase (NDM-1) has even been reported in drinking water from New Delhi (Walsh, T.R., et al., 2011). Prevalence of asymptomatic EPE carrier ship varies within different regions of the world. In Sweden, the reported prevalence was 4.8% for samples collected 2012-2013 (www.folkhalsomyndigheten.se/documents/nyheterpress/nyheter2014/MSBESBL slutrapport.pdf).

In Thailand a prevalence as high as 65.7% was reported from rural areas (Luvsansharav, U.O., et al., 2012). The carrier ship was 19% in a tribal area in India in a study from 2015 (Mathai, D., et al., 2015) while surveillance rectal swabs in outpatients presenting to pediatric oncology unit revealed high EPE carrier ship, 58.4%, with a rate of  CPE carriers of 20.2% (Thacker, N., et al., 2014). Altogether resistance rates over 50% against extended-spectrum cephalosporins have now been described in all WHO regions, albeit with considerable variation within the regions (Available at: www.who.int/drugresistance/documents/surveillancereport/en/).

International travel has been associated with high frequency of EPE Acquisition in several prospective studies. Traveling to southern Asia, including India, poses a particularly high risk. Diarrhea and use of antibiotics during the trip have been considered independent risk factors for acquisition (Tangden, T., et al., 2010; Ruppé, E., et al., 2015; Ostholm-Balkhed, A., et al., 2013; Kantele, A., et al., 2015; Angelin, M., et al., 2015; Kuenzli, E., et al., 2014; and Lubber, C., et al.,). It is a prospective study on 188 Swedish travelers to four geographic areas with an expected high prevalence of EPE; Southeast Asia, the Indian subcontinent, Northern Africa and the Middle East (all travelers to this region went to Turkey). The study aimed to investigate the molecular features of EPE colonizing the gut after travel and to determine risk factors for colonization. The travelers submitted one fecal sample before the trip and one upon return and answered two questionnaires. EPE strains were characterized with molecular methods.

2.8.6 Carbapenemase – Producing Enterobacteriaceae

1993 was the first time carbapenemase production was detected in Enterobacteriaceae.

It was in a clinical isolate of Enterobacter cloacae, a chromosomally encoded NmcA (Munoz-Price, L.S., et al., 2013). Since then a large variety of plasmid-mediated CPEs has been identified. The carbapenemases belong to the Ambler class A, B, and D.

2.8.7 Global dissemination of CPE

 

KPC enzymes were first detected in a  isolate in the United States in 1996, showing resistance to all ?-lactams. In the early 2000s epidemic, outbreaks of CPE were reported from Greece, the USA, and later from Israel. KPC is now endemic in Greece, and the most common carbapenemase among Enterobacteriaceae in Europe, but have also disseminated in South America and China (Kitchel, B., et al., 2009; and Watanabe, M., et al., 1991). In data from EARS-net, 62% of invasive  isolates reported from Greece in 2014 were non-susceptible to carbapenems. In Italy, an outbreak of KPC among  resulted in an increase of carbapenem resistance in invasive  from one to 27 % between 2009 and 2011. In 2014 the rate had increased further up to 33 % (http://ecdc.europa.eu).  KPC is most common in  but can also be expressed by other Enterobacteriaceae as well as by Pseudomonas aeruginosa. KPC is associated with the worldwide disseminated ST258 Lauretti, L., et al., 1999).

The Metallo-?-lactamases include IMP, VIM (Verona integron-encoded Metallo-?lactamase), and NDM (New Delhi Metallo-?-lactamases) enzymes. IMP was first recognized in Japan in the end of the 1980s in Pseudomonas aeruginosa (Cornaglia, G., H. Giamarellou, and G.M. Rossolini, 2011). A VIM-positive isolate was first observed in P. aeruginous in Verona, Italy, in late 1997 (Kumarasamy, K.K., et al., 2010), and later disseminated to other Enterobacteriaceae, especially . VIM is still common in Greece but has been reported also from many other parts of the world (Walsh, T.R., et al., 2011). NDM-1 was described for the first time in 2010 (Dortet, L., L. Poirel, and P. Nordmann, 2014), originating from the Indian subcontinent. NDMs are highly prevalent on the Indian subcontinent and in the Middle East with prevalence rates of NDM-producers among Enterobacteriaceae ranging from 5 to 18.5% in Indian and Pakistani hospitals. It has also been detected in drinking water and seepage samples in New Delhi (Canton, R., et al., 2012).

NDM has been imported into European countries on several occasions, mainly detected in hospitalized patients transferred from endemic areas. As NDM is being reported not only in , but also in  they entail a high risk both for dissemination in the community, and to cause community-acquired infections. NDMs are also seen in Acinetobacter sp and, more rarely, in P. aeruginosin (Poirel, L., et al., 2004; Poirel, L., A. Potron, and P. Nordmann, 2012). Oxacillinase-type ?-lactamase (OXA-48) enzyme was for the first time identified in a carbapenem-resistant  in Turkey in 2001 (Organization WHO 2014). After that OXA-48-like enzyme have emerged and disseminated in mainly Northern Africa and the Middle East, but also caused outbreaks in several European countries such as the UK, France, Germany, Belgium and the Netherlands (Ruppé, E., et al., 2014). They are still mostly detected among  but have also been reported in other species. Strains containing OXA-48-like enzymes often express only discrete elevation of carbapenem minimal inhibitory concentration (MIC) (Ruppé, E., et al., 2014), challenging Carbapenemase production is so far more common in  than in  isolates in most European countries as well as in other geographical regions. Although high rates of CPE are reported from the regions visited in paper IV (Ramirez, M.S. and M.E. Tolmasky, 2010), none of the travelers’ acquired CPE. To this date, there are only

 a few reports of healthy travelers acquiring carbapenemase-producers (Wei, D.D., et al., 2015).

One possible explanation is that CPE still is more common among  compared to , which is the bacteria most commonly acquired in the community. If carbapenem resistance rates increases in the  population in the future, the dissemination in the community will probably speed up. Lack of effective therapies against common community-acquired infections caused by  will also increase with such scenario.

2.8.8 Plasmid-Mediated Non- B-lactam Resistance

Plasmid-medicated co-resistance to other antibiotic groups often occurs in EPE. Some of the clinically most important are presented below.

The modes of transmission of resistance genes between bacterial strains are similar to those of ?-lactam resistance.

2.8.9 Plasmid-mediated amino glycoside resistance

The most common mechanism is the production of aminoglycoside-modifying enzymes (AMEs). Several AMEs exist, the most common plasmid-mediated in Enterobacteriaceae is aminoglycoside acetyltransferase, encoded by Aac (6´). Expression of Aac (6´) can confer resistance both to amikacin and gentamicin, although not compulsory (Martinez-Martinez, L., A. Pascual, and G.A. Jacoby, 1998). The Plasmid-mediated 16S rRNA methylase provides high-level resistance to aminoglycoside antibiotics including not only gentamicin but also amikacin and tobramycin. There are several 16S methylase genes, including armA, rmtA, rmtB, rmtC, and rmtD (Liu, Y.Y., et al., 2015).

2.8.10 Plasmid-mediated quinolone resistance

 

            In 1998 qnrA, a plasmid-mediated quinolone resistance gene was found for the first

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