different esbl genotypes have different substrate specificities for the many -lactam antibiotics ( 11 ) , also between ctx - m enzymes . as mentioned bla 
 ctx - ms are found all over the world and bla 
 ctx - m-15 is the most dominating genotype ( 12 ) . the distribution of genotypes is homogenous . in sweden , 5060% of esbl - producing e. coli harbor bla 
 ctx - m-15 followed by bla 
 ctx - m-14 found in 1015% ( 7 ) . in norway and denmark , about 50% and 20% of the genotypes are bla 
 ctx - m-15 and bla 
 ctx - m-14 respectively ( 13 , 14 ) . the esbl epidemiology in finland has been sparsely reported , but a predominance of the ctx - m-1 group ( including bla 
 ctx - m-15 ) is found ( 15 , 16 ) . in other parts of europe , , there is a high level of bla 
 ctx - m-14 and bla 
 ctx - m-9 , and in poland as well as several other eastern european countries bla 
 ctx - m-3 has been reported as frequent ( 17 , 18 ) . in the african and australian continents , bla 
 ctx - m-15 is also the most frequent and increasingly so in the united states of america , where bla 
 shv - phenotypes used to be the most encountered ( 20 ) . the ctx - m-9 phylogroup is largely dominating ( 21 ) and also in china bla 
 ctx - m-14 is more commonly reported ( 22 ) . in india , south america stands out with a wide distribution of the ctx - m 2 phylogroup . also the ctx - m-8 phylogroup is found in south america which is rare on other continents ( 12 , 19 ) . transmission of genes encoding esbl enzymes can occur either by emerging bacterial clones or by horizontal gene transfer . in the latter case , plasmids containing resistance genes are spread between bacteria of the same and/or different species . the gut flora is an ideal reservoir for antibiotic resistance genes , where kilograms of bacteria of different species can interact , most often without causing disease and hence to much interference with the immune system . clonal expansion refers to a particular bacterial cell line multiplying and disseminating in a community or causing an outbreak , for example , in a hospital . rapid detection of clonal expansions is important in order to be able to stop or diminish the source of dissemination . an example of clonal expansion is the e. coli sequence type 131 ( st131 ) that is found globally ( 25 ) . st131 is highly associated to bla 
 ctx - m-15 
 ( 25 ) . in the nordic countries , st131 represents 2040% of the esbl - producing e. coli ( 13 , 14 , 26 ) . however , st131 is also found in non - esbl e. coli , suggesting that st131 is a dominant e. coli type that has acquired esbls which may have contributed to the successful dissemination of these resistance genes ( 25 . an example is the sts of clonal complex 11 ( cc11 ) which have been associated to ctx - m dissemination ( 4 , 27 ) . the uppsala outbreak , in 2005 , was due to a bla 
 ctx - m-15 producing k. pneumoniae that was spread over several ward departments of the university hospital . another large outbreak of bla 
 ctx - m-15 producing k. pneumoniae occurred in a neonatal ward department of stavanger university hospital in 20082009 . fifty - eight infants were infected , probably for receiving contaminated breast milk ( 29 ) . although st131 represent a large fraction of the esbl - producing e. coli population , still ~50% of swedish isolates are genetically unrelated isolates . this indicates that horizontal gene transfer is a major route for disseminating esbls and that these resistance genes have a remarkable ability to enter e. coli of many different back - bones ( 7 ) . plasmids are double - stranded extra - chromosomal dna that replicate independently of the chromosome in the bacterial cell hosting it . plasmids are highly diverse and the plasmid genome is often scattered with mobile genetic elements that can move genes around within the plasmid as well as between chromosome and plasmid(s ) . examples of mobile genetic elements found on plasmids are is - elements , transposons , integrons and insertion sequence common regions ( iscr ) , of which the latter is associated to esbl genes . antitoxin systems that act by eliminating cells that have lost the plasmid after cell division ( 24 ) . figure 1 pictures a schematic illustration of plasmid conjugation which is a common route for plasmid dissemination . plasmids can be classified according to incompatibility ( inc ) groups , which are based on the principle that plasmids with the same replicon can not be propagated stably in the same cell ( 30 ) . the explanation for this is that similar plasmids compete over common cellular functions involved in , for example , plasmid replication control ( 31 ) . a replicon is a highly conserved part of the plasmid where genes encoding replication initiation , control , copy number , etc . nowadays incompatibility grouping have been replaced by replicon typing which is simpler experimentally and also allows for a subdivision of some of the inc groups . one example is the incf1 plasmids that include repfia , fib and fic of which repfia and fib plasmids are commonly found to harbor esbl genes . a schematic illustration of a plasmid . inca / c plasmids , found associated to esblm and esblcarba , are contrarily broad host range plasmids that are found in a wide variety of bacterial species . these are incf , inca / c , incl / m , incn and inci ( 32 ) . among fully sequenced e. coli plasmids harboring bla 
 ctx - m - genes in genbank , the following plasmid families are found : incf , incn , incn2 , inci1 , inchi2 , incl / m , inca / c , inck , incx4 , incu and rcr ( 33 ) . in norwegian and swedish , esbl - producing e. coli incf plasmids are almost exclusively found ( 13 , 34 ) . subtyping by replicon sequence typing ( rst ) however shows a great variability within f - plasmids , and it is not possible to link a specific incf - plasmid to the successful dissemination of bla 
 ctx - ms 
 ( 35 ) . incf plasmids are found also in antibiotic - sensitive enterobacteriaceae suggesting that the esbl genes have entered an already well - established plasmid type which has been beneficial for their dissemination ( 36 ) . clonal expansion refers to a particular bacterial cell line multiplying and disseminating in a community or causing an outbreak , for example , in a hospital . rapid detection of clonal expansions is important in order to be able to stop or diminish the source of dissemination . an example of clonal expansion is the e. coli sequence type 131 ( st131 ) that is found globally ( 25 ) . st131 is highly associated to bla 
 ctx - m-15 
 ( 25 ) . in the nordic countries , st131 represents 2040% of the esbl - producing e. coli ( 13 , 14 , 26 ) . however , st131 is also found in non - esbl e. coli , suggesting that st131 is a dominant e. coli type that has acquired esbls which may have contributed to the successful dissemination of these resistance genes ( 25 . an example is the sts of clonal complex 11 ( cc11 ) which have been associated to ctx - m dissemination ( 4 , 27 ) . the uppsala outbreak , in 2005 , was due to a bla 
 ctx - m-15 producing k. pneumoniae that was spread over several ward departments of the university hospital . another large outbreak of bla 
 ctx - m-15 producing k. pneumoniae occurred in a neonatal ward department of stavanger university hospital in 20082009 . fifty - eight infants were infected , probably for receiving contaminated breast milk ( 29 ) . although st131 represent a large fraction of the esbl - producing e. coli population , still ~50% of swedish isolates are genetically unrelated isolates . this indicates that horizontal gene transfer is a major route for disseminating esbls and that these resistance genes have a remarkable ability to enter e. coli of many different back - bones ( 7 ) . plasmids are double - stranded extra - chromosomal dna that replicate independently of the chromosome in the bacterial cell hosting it . plasmids are highly diverse and the plasmid genome is often scattered with mobile genetic elements that can move genes around within the plasmid as well as between chromosome and plasmid(s ) . examples of mobile genetic elements found on plasmids are is - elements , transposons , integrons and insertion sequence common regions ( iscr ) , of which the latter is associated to esbl genes . antitoxin systems that act by eliminating cells that have lost the plasmid after cell division ( 24 ) . figure 1 pictures a schematic illustration of plasmid conjugation which is a common route for plasmid dissemination . plasmids can be classified according to incompatibility ( inc ) groups , which are based on the principle that plasmids with the same replicon can not be propagated stably in the same cell ( 30 ) . the explanation for this is that similar plasmids compete over common cellular functions involved in , for example , plasmid replication control ( 31 ) . a replicon is a highly conserved part of the plasmid where genes encoding replication initiation , control , copy number , etc . nowadays incompatibility grouping have been replaced by replicon typing which is simpler experimentally and also allows for a subdivision of some of the inc groups . one example is the incf1 plasmids that include repfia , fib and fic of which repfia and fib plasmids are commonly found to harbor esbl genes . a schematic illustration of a plasmid . the host range of plasmids is largely determined by the inc type . inca / c plasmids , found associated to esblm and esblcarba , are contrarily broad host range plasmids that are found in a wide variety of bacterial species . these are incf , inca / c , incl / m , incn and inci ( 32 ) . among fully sequenced e. coli plasmids harboring bla 
 ctx - m - genes in genbank , the following plasmid families are found : incf , incn , incn2 , inci1 , inchi2 , incl / m , inca / c , inck , incx4 , incu and rcr ( 33 ) . plasmid variability within incompatibility groups is high . in norwegian and swedish , esbl - producing e. coli incf plasmids subtyping by replicon sequence typing ( rst ) however shows a great variability within f - plasmids , and it is not possible to link a specific incf - plasmid to the successful dissemination of bla 
 ctx - ms 
 ( 35 ) . incf plasmids are found also in antibiotic - sensitive enterobacteriaceae suggesting that the esbl genes have entered an already well - established plasmid type which has been beneficial for their dissemination ( 36 ) . the nordic countries are considered low prevalence countries , but the epe numbers are increasing fast . in sweden , national surveillance has been performed since 2007 when esbls were included in the communicable disease act . the number of cases have increased from 2099 in 2007 ( feb  dec ) to 8131 in 2013 . several studies pictures the local frequency in different parts of sweden ; helldal et al . described the prevalence of esbl - producing e. coli in south western sweden during 20042008 with a higher increase in nosocomially acquired isolates in comparison to community - acquired , 0.22.5% and 0.21.6% , respectively ( 37 ) . a study from the county of stergtland indicated an increased prevalence of epe from 2002 to 2007 , yet the numbers were very low ( < 1% ) ( 38 ) . an investigation of the fecal carriage of esbl - producing bacteria in both primary health care units and university hospital setting in southern sweden was conducted in 20082010 . the only species found was e. coli , and the authors described the prevalence as higher than expected in both groups , 2.13% and 1.86.8% , respectively ( 39 ) . a recent study from uppsala investigated the prevalence of epe in healthy preschool children compared to patients in the same age group . the authors found a carrier rate of 2.9% in healthy children compared to 8.4% in patients of the corresponding age group ( 40 ) . in helsinki , finland , the annual incidence rate of epe has gone from 0.5/100 000 inhabitants in the year 2000 to 69/100 000 in 2004 ( 15 ) . in denmark , the rate of invasive epe has increased from 2.5% in 2006 to 6.2% in 2009 ( 41 ) . the annual report of antibiotic resistance isolates in norway , norm / norm - vet , published in 2012 states that epe is increasing steadily , and the number of epe in blood cultures has increased from 3.3% in 2011 to 5.5% in 2012 ( 42 ) . in europe , the prevalence of bacteria resistant to extended spectrum cephalosporins differs a lot between countries . they are less frequent in the north and more common in the southern and eastern parts of europe . the european network of national surveillance systems of antimicrobial resistance summarizes the levels of invasive infections caused by resistant bacteria in the european countries in a yearly report available on the ecdc homepage : http://ecdc.europa.eu/. the results are also illustrated on color - coded maps . in fig . 3 , levels of invasive e. coli infections resistant to third - generation cephalosporins are illustrated over time . however , one must keep in mind that the results are biased by differences in reporting , national monitoring and sampling . maps generated by ears - net illustrating the proportion of invasive e. coli isolates resistant or intermediately resistant to third - generation cephalosporins from reporting countries in a ) 2001 and b ) 2012 . a recent study from the usa presents results from the sentry surveillance program including 26 hospitals from 20 states . the resistance levels to cephalosporins and/or aztreonam in invasive enterobacteriaceae was 6.4% ( 43 ) . a canadian study reported esbl - production in almost 5% of the e. coli population the level of resistant bacteria is truly troublesome in other parts of the world . in thailand , carriage of esbl - producing bacteria , in as high numbers as 52% of healthy volunteers , has been reported ( 45 ) . in india , the reports are also alarming with high numbers seen among patients . a study from two hospitals in ujjain , india , collected consecutive isolates from incoming patients with abscesses , uti , bsi , etc . and found esbl production in 69% of e. coli ( 46 ) . one factor contributing to the low epe numbers in the nordic countries is the restricted antibiotic treatment policies . despite the strict antibiotic policy and decreasing antibiotic consumption , epe is still increasing ( 47 ) . it has been shown that one entry of epe to low prevalence countries is through traveling to countries with higher prevalence . in 2010 , tngden et al . studied the acquisition of resistance genes as a result of travel outside northern europe . the study resulted in 24% returning as new carriers of epe after travel ( 48 ) . patients admitted to an infectious disease department in aarhus , denmark , who had been abroad within 3 months were identified and subjected to screening for multidrug resistant bacteria . epe colonization was found in 12.5% of which > 80% had been abroad for longer than 2 weeks ( 49 ) . many countries outside scandinavia ( e.g. the member states of the european union ) also have antibiotic prescribing policies where prescription is required for antibiotics to be purchased . acquisition of antibiotics  over the counter in pharmacies or equivalents still occurs in many places . infection control routines and programs have a large impact on dissemination of bacteria ( 5052 ) . differences in infection control routines are substantial between different countries , also between european countries . . if awareness of the regional situation is low , preventive measures will also be . more and more studies show that there is dissemination of bacteria between food , animal ( both food - production animals and pets ) and humans ( 5356 ) . consequently antibiotic usage and inadequate infection control in veterinary medicine , fish farming , irrigation , etc . also contribute to the increased spread of antibiotic resistance . fecal cultures represent a snapshot of the flora at the time of study , and low numbers of bacteria can be difficult to detect . it has been shown that a person can present several negative samples and then later on still come up with a positive one ( 57 ) . one example is lhr et al . who have followed children and their family members for 3 years after an outbreak in the neonatal intensive care unit in stavanger , norway . the authors observed carrier length of up to 2 years in some of the children ( 58 ) . persistence in neonates is proposed to be longer than in older children and adults since they have not yet established a naturally protective microbial flora . they also have an undeveloped immune system and are more often treated with antibiotics ( 58 ) . alsterlund et al . studied epe fecal colonization after a hospital outbreak in southern sweden and found some individuals to still be colonized after 5 years ( 57 ) . another swedish study by tham et al . describes persistence of esbl in 10% of patients after 3 years . the authors detected two new esbl - producing strain types in one of the patients indicating transfer of the resistance phenotype ( 59 ) . an alternative interpretation would be that this patient was infected with additional strains , although given the low frequency of epe in sweden the probability seems low . low risk of re - colonization is beneficial when studying colonization rates , since the probability of finding the true colonization rate , duration of carriage and migration of plasmids between species increases . studied persistence of epe in 61 patients over the course of 1 year . by the end of the study period , some of the patients presented epe of different species and molecular strain types carrying the same resistance gene over time picturing the interaction between the bacteria in the git . colonization in other patients in the same study , however , presented one identical strain type with the same resistance gene over time ( 60 ) . a spanish study reported that 16.7% of people living together with persons with known community - acquired infections also were colonized ( 61 ) . these numbers can be compared with a control group of unrelated persons where the carrier rate was 7.4% ( 62 ) . a chinese study investigated esbl carriage in children 05 years of age admitted to a pediatric clinic in hong kong and found ctx - m producing bacteria in 43.5% . in 83% of these children , at least one of the household members was also a carrier ( 63 ) . a french study found intra - family transmission from adoptive children to their new family members at a rate of 23% ( 64 ) . investigated a plasmid , pct , harboring bla 
 ctx - m-14 ( the only resistance gene on that plasmid ) . they transformed the plasmid into an e. coli strain and found that it provided little or no additional fitness to the bacteria , but still the plasmid persisted successfully in the absence of selective antibiotic pressure . this suggests that persistence of the plasmid is not always dependent on the resistance gene ( 65 ) . dissemination through plasmids adds a second dimension to this problem , and most probably prolongs the ability for resistance phenotypes to persist . the impact of antibiotic treatment on the dissemination and persistence of resistant bacteria can not be underestimated . in order to use these extremely important drugs as rational as possible , we need to gain full understanding of how resistance arises and all the factors that influence dissemination . optimized antibiotic treatment is in turn dependent on the development of faster diagnostic tools in order to minimize empirical treatment . strain and plasmid interaction and dissemination needs further attention in order to be fully understood . . such knowledge would contribute to important information regarding how to handle patients colonized with epe in hospitals and for how long persistence is to be expected under different conditions . it could also give us insight in how to optimize antibiotic treatment to be as effective as possible for patients and yet minimize further antibiotic resistance from arising and disseminating . for antibiotics to be potent also in the future , promoting rational antibiotic use in all sectors minimizes the selective pressure for resistant bacteria . new antibiotic agents are also needed as well as optimizing the usage of the already available antibiotics . new treatment options can buy us time to address this important issue that constitutes a major public health problem .
extended spectrum -lactamases ( esbl ) are increasing rapidly worldwide . 
 e. coli producing ctx - m type esbls are the most common clinically encountered . the majority of e. coli esbl infections 
 are represented by urinary tract infections , but they can also cause severe infections , for example , in the blood stream and central nervous system . since e. coli is a common colonizer of the normal gut microbiota , increasing prevalence of esbl - producing strains is particularly worrisome . 
 once disseminated in the community , containment of this resistance type will be challenging . 
 the driver of esbl - producing enterobacteriaceae ( epe ) is debated . 
 some suggest that the esbl genes were introduced to particularly successful bacterial clones . 
 others imply that very successful plasmids drive the rapid dissemination . more research and epidemiological studies of strain types , plasmids and mobile genetic elements 
 are needed for these questions to be answered . in order to combat , or at least slow down , the worrisome trend of increasing numbers of epe more knowledge 
 is also needed on persistence of epe in carriers as well as better understanding of how antibiotic treatment and other risk factors affect persistence and further dissemination . 
 this review aims at giving an overview of this global problem from a nordic perspective .