TY - JOUR
AU1 - Su, Lin-Hui
AU2 - Chu, Chishih
AU3 - Cloeckaert, Axel
AU4 - Chiu, Cheng-Hsun
AB - Abstract CTX-M- and AmpC-type β-lactamases comprise the two most rapidly growing populations among the extended-spectrum cephalosporinases. The evolution and dissemination of resistance genes encoding these enzymes occur mostly through the transmission of plasmids. The high prevalence of clinical isolates of Enterobacteriaceae producing the plasmid-mediated extended-spectrum cephalosporinases resembles an epidemic of plasmids, and has generated serious therapeutic problems. This review describes the emergence and worldwide spread of various classes of plasmid-mediated extended-spectrum cephalosporinases in Salmonella and other Enterobacteriaceae, the transfer mechanism of the plasmids, detection methods, and therapeutic choices. plasmid, antimicrobial resistance, extended-spectrum β-lactamase, AmpC, Salmonella, Enterobacteriaceae Introduction Many Gram-negative bacteria are able to express chromosome-mediated β-lactamases, which represent a major resistance mechanism to β-lactam antibiotics. The first plasmid-mediated β-lactamase to be discovered, TEM-1, was described in 1965 (Datta & Kontomichalou, 1965). The subsequently discovered TEM-2 and TEM-13 were derived from TEM-1 with a similar hydrolytic spectrum (Jacoby & Medeiros, 1991). SHV-1 is another widespread plasmid-mediated β-lactamase; its hydrolytic spectrum of activity is similar to that of TEM-1, but it achieves better activity against ampicillin (Bush et al, 1995). SHV-1-related sequences can be found on the chromosome of most strains of Klebsiella pneumoniae (Haeggman et al, 1997). This may explain the common ampicillin resistance expressed by this organism, and also suggests that the K. pneumoniae species-specific chromosomal β-lactamase is the ancestor of plasmid-mediated SHVs. In some way, possibly as a result of environmental selective pressure, the gene was transferred into a plasmid where it acquired the potential for horizontal dissemination to other bacterial species. These early plasmid-mediated β-lactamases are broad-spectrum β-lactamases capable of hydrolyzing both penicillins and narrow-spectrum cephalosporins (Bush et al, 1995). However, the capture of the gene by the plasmid has facilitated the widespread distribution of such resistance determinants among many bacterial species, leading to subsequent global dissemination. The development of the third-generation, or extended-spectrum, cephalosporins in the early 1980s was a milestone in the history of the battle against the antimicrobial resistance of pathogenic bacteria, because these antimicrobial agents initially were resistant to all known β-lactamases, which are frequently produced by many Gram-negative bacteria. However, many hospital epidemics since then have been described to be related to the spread of multidrug-resistant bacteria under the selective pressure of extensive use of extended-spectrum cephalosporins (Bradford, 2001; Paterson & Bonomo, 2005). The major mechanism for the spread of such resistance among members of the family Enterobacteriaceae is also associated with the transfer of resistance plasmids. This review aims to provide an overview of the emergence and wide dissemination of several major classes of plasmid-mediated extended-spectrum cephalosporinases in Enterobacteriaceae, the mechanisms by which the resistance plasmids disseminate, and the clinical impact of the production of these enzymes on laboratory detection and therapy. Emergence of extended-spectrum cephalosporinases The first plasmid-encoded β-lactamase to be defined that is capable of hydrolyzing the extended-spectrum cephalosporins was SHV-2 (Kliebe et al, 1985). Sequence analysis indicated that SHV-2 differed from SHV-1 by only one mutational change, resulting in the replacement of glycine by serine at codon 238 as well as in a substantial expansion of its hydrolytic spectrum. Since then, other extended-spectrum cephalosporin-hydrolyzing β-lactamases have been discovered and increasingly described in several species of Enterobacteriaceae (Bradford, 2001; Paterson & Bonomo, 2005). These new β-lactamases have collectively been termed extended-spectrum β-lactamases (ESBLs). Historically, however, the first appearance of ESBLs can be traced back to as early as 1982, when a strain of Klebsiella oxytoca demonstrating ceftazidime resistance was recovered in England (Du Bois et al, 1995). The β-lactamase responsible, reported in 1995 as TEM-12, was carried on a plasmid. The subsequent dissemination of such plasmid-mediated resistance to extended-spectrum cephalosporins was so fast that it soon affected several bacterial species. To date, such reports have been described in many countries, and several continents have been affected. Plasmid-mediated resistance is one of the most important problems of antimicrobial resistance that has been encountered in the past two decades. Following the introduction of more β-lactam antibiotics with greater β-lactamase stability, including the fourth-generation cephalosporins, carbapenems and monobactams in the late 1980s, some Gram-negative bacteria, notably Citrobacter freundii, Enterobacter cloacae, Escherichia coli, Morganella morganii, Providencia rettgeri, and Serratia marcescens, evolved by mutation to overexpress their chromosomal AmpC-type β-lactamases, thus providing resistance to extended-spectrum cephalosporins and monobactams (Sanders, 1987; Caroff et al, 2000; Philippon et al, 2002; Walther-Rasmussen & Høiby, 2002). Worst of all, such resistance phenotypes soon appeared in other species, including K. pneumoniae, Proteus, Salmonella and Shigella, that lack an intrinsic AmpC-type enzyme; the spread of this resistance was also mediated by plasmids (Chiu et al, 2004; Huang et al, 2005; Su et al, 2005, 2006; Su & Chiu, 2007; Wu et al, 2007). AmpC-type β-lactamases, when encoded by genes originally located on the chromosome, are inducible via a regulation system, which primarily involves AmpR (Philippon et al, 2002). Until recently, plasmid-encoded ampC genes were thought to be noninducible owing to the lack of a functional ampR gene or the absence of an AmpR binding site (Philippon et al, 2002). However, plasmid-encoded blaDHA genes originating from M. morganii are nearly always mobilized together with ampR (Verdet et al, 2006). Similar situations are found in other inducible plasmid-mediated non-DHA ampC genes, including ACT-1 (Reisbig & Hanson, 2002), CFE-1 (Nakano et al, 2004), and CMY-13 (Miriagou et al, 2004). The mechanism that determines whether the ampC alone or ampC together with ampR are to be mobilized from a chromosome onto a plasmid needs further study. Classification of extended-spectrum cephalosporinases Plasmid-mediated extended-spectrum cephalosporinases can be grossly divided into two groups, ESBLs and AmpC-type β-lactamases, according to the source of origin, spectrum of hydrolysis, and susceptibility to β-lactamase inhibitors. There are currently more than 300 ESBLs that have been described. To maintain the most up-to-date information and standardize the nomenclature for this rapidly growing population, a website (http://www.lahey.org/studies/webt.htm) hosted by George Jacoby and Karen Bush has been established and made accessible to the public. According to the latest revision of the website as of 28 November 2007, the two largest ESBL families are TEM-type derivatives, which have reached TEM-161, and SHV-type derivatives, which have reached SHV-105. All of them are the progeny of classical β-lactamases, TEM-1, TEM-2, or SHV-1, which are not ESBLs. The early predominance of TEM- and SHV-type variants among ESBLs appears to reflect the widespread distribution of their plasmid-bound ancestor enzymes (TEM-1 and SHV-1) in the 1970s. In addition to SHV- and TEM-type enzymes, other types of plasmid-mediated ESBLs have increased dramatically in recent years. Among them, CTX-M-type β-lactamases represent the most rapidly growing group of ESBLs (Bonnet, 2004; Walther-Rasmussen & Høiby, 2004). The first CTX-M-like ESBL to be discovered, designated FEC-1, was from a cefotaxime-resistant isolate of E. coli in Japan in 1986 (Matsumoto et al, 1988). In 1989 in Germany, Bauernfeind (1990) reported the discovery of a non-TEM, non-SHV ESBL, designated CTX-M-1, from a clinical cefotaxime-resistant E. coli isolate. Although the appearance of CTX-M enzymes was only a few years later than that of TEM- or SHV-type ESBLs, the global expansion of CTX-M-producing strains was not found until 1995 (Bonnet, 2004; Walther-Rasmussen & Høiby, 2004). The CTX-M-type derivatives have now reached CTX-M-69, and only CTX-M-1 and CTX-M-2 were identified before 1995 (Bauernfeind et al, 1990, 1992). Owing to the high homology in the sequences of these β-lactamase genes and the surrounding genetic environment, the chromosomal cephalosporinases of Kluyvera spp. are considered to be the progenitors of the plasmid-encoded CTX-M-type ESBLs (Decousser et al, 2001; Humeniuk et al, 2002; Poirel et al, 2002). Other minor ESBL families have also been reported, including the PER, VEB, TLA, GES, and IBC types that preferentially hydrolyze ceftazidime (Vahaboglu et al, 1995; Bauernfeind et al, 1996; Poirel et al, 1999, 2000; Silva et al, 2000; Girlich et al, 2001; Vourli et al, 2003), and the SFO, BES, and FEC types that preferentially hydrolyze cefotaxime (Matsumoto et al, 1988; Matsumoto & Inoue, 1999; Bonnet et al, 2000). These ESBLs are probably plasmid-encoded and have been found in a wide range of geographic locations. Recent reports, however, have indicated that genes encoding PER-1 can be found inserted into the chromosome of isolates in some members of the family Enterobacteriaceae (Perilli et al, 2007). VEB, TLA, GES, and IBC genes also can be found located in integrons (Poirel et al, 1999; 2000; Girlich et al, 2001; Vourli et al, 2003; Szczepanowski et al, 2004; Bae et al, 2007). Plasmid-mediated AmpC β-lactamases represent another large group of extended-spectrum cephalosporinases that are of great clinical concern. The nomenclature of plasmid-mediated AmpC β-lactamases is much more complicated than that of ESBLs (Philippon et al, 2002). On the basis of amino acid similarities as well as of their putative progenitor chromosomal enzymes, these plasmid-mediated AmpC β-lactamases can be classified into distinct genetic clusters (Pérez-Pérez & Hanson, 2002; Philippon et al, 2002; Walther-Rasmussen & Høiby, 2002): the Aeromonas caviae group with FOX-type enzymes; the Aeromonas spp. group with MOX types and certain CMY types (CMY-1, -8 to -11, etc.); the C. freundii group with BIL-, CFE-, LAT-, and some CMY-type enzymes (CMY-2 to -7, etc.); the E. cloacae group with ACT and MIR types; the Hafnia alvei group with ACC types; and the M. morganii group with DHA types. Plasmids encoding these AmpC β-lactamases were all derived from the chromosomally encoded AmpC β-lactamases of the individual representative bacterial species. Global dissemination The early appearance of ESBLs in Europe may reflect the fact that clinical use of extended-spectrum cephalosporins started in this region. The phenomenon soon proliferated to become a global epidemic, as it did not take long for countries in other parts of the world to report the emergence of various ESBL-producing bacteria. However, the prevalence of ESBL production varies significantly among bacterial species and ESBL types as well as among countries and institutions. The SENTRY Antimicrobial Surveillance Program has been established for several years to monitor the prominent pathogens and antimicrobial resistance patterns of nosocomial and community-acquired infections via a broad network of sentinel hospitals distributed by geographic location. The most recent reports from the SENTRY data are summarized in Table 1 and may represent the current global status of ESBL production among the Enterobacteriaceae (Winokur et al, 2001; Bell et al, 2003; Nijssen et al, 2004; Hirakata et al, 2005; Deshpande et al, 2006). In general, the highest rate of ESBL production was found in K. pneumoniae, particularly among isolates recovered from eastern and southern Europe, Latin America, and some countries in the Asia-Pacific region (Winokur et al, 2001; Nijssen et al, 2004; Hirakata et al, 2005). Escherichia coli isolates from these areas also expressed a relatively higher rate of ESBL production. Similar findings have been reported from another large series of antimicrobial susceptibility surveillance programs — the Meropenem Yearly Susceptibility Test Information Collection (MYSTIC) study (Turner, 2004). Table 1 Percentage of organisms expressing an ESBL phenotype in the SENTRY Antimicrobial Surveillance Program for various regions and countries in the past decade     No. of isolates tested and rate (%) of isolates with an ESBL phenotype        Total  Escherichia coli  Klebsiella pneumoniae  Klebsiella oxytoca  Proteus mirabilis  Enterobacter cloacae  Year(s) of study  Region Country  No.  %  No.  %  No.  %  No.  %  No.  %  No.  %  References  1997–1998  Europe  4707  4.9  3325  1.3  767  18.1  215  12.6  400  5.3      Nijssen (2004)    France  1020  1.1  776  0  117  4.3  36  8.3  91  3.3          Spain  799  1.6  581  0.3  104  5.8  38  10.5  76  1.3          Germany  466  1.1  341  0  70  2.9  31  9.7  24  0          Greece  357  12.6  220  2.0  94  38  9  22.2  34  5.9          Italy  320  11.9  219  7.0  40  30.0  16  12.5  45  28.9          Switzerland  303  0.7  228  0.9  47  0  17  0  11  0          Turkey  294  23.8  172  8.0  103  48.5  14  42.9  5  0          The Netherlands  279  2.5  173  0  48  8.3  24  12.5  34  0          Portugal  230  10  145  5.0  69  23.2  0  0  16  0          Poland  217  4.6  159  2.0  33  15.2  7  14.3  18  5.6          Austria  137  0.7  105  0  16  0  8  12.5  8  0          Belgium  117  1.7  84  0  12  0  12  16.7  9  0        1998−2002  Asia Pacific      3655  5.9  1738  17.3  250  6.8  338  3.3  587  16  Bell (2003),    Australia      1311  0.5  328  3.7  130  0.8  151  0  178  4  Hirakata (2005)    China      163  24.5  75  30.7  10  30.0  9  0  38  37      Hong Kong      608  14.3  224  11.6  10  0  37  8.1  36  6      Japan      337  2.4  210  10.0  51  5.9  27  3.7  101  3      Philippines      338  5.0  319  21.9  13  38.5  33  0  94  35      Singapore      318  11.3  225  35.6  3  33.3  39  17.9  27  44      South Africa      261  1.5  135  28.1  16  0  27  0  54  20      Taiwan      319  5.6  222  13.5  17  23.5  15  0  59  19    1997−1999  Western Pacific      1104  7.9  560  24.6      111  1.8      Winokur (2001)    Europe      3822  5.3  946  22.6      442  11.1          Latin America      2026  8.5  897  45.4      196  22.4          United States      4966  3.3  2017  7.6      589  4.9          Canada      1203  4.2  368  4.9      97  3.1        2004  North America      1429  4.5                  Deshpande (2006)      No. of isolates tested and rate (%) of isolates with an ESBL phenotype        Total  Escherichia coli  Klebsiella pneumoniae  Klebsiella oxytoca  Proteus mirabilis  Enterobacter cloacae  Year(s) of study  Region Country  No.  %  No.  %  No.  %  No.  %  No.  %  No.  %  References  1997–1998  Europe  4707  4.9  3325  1.3  767  18.1  215  12.6  400  5.3      Nijssen (2004)    France  1020  1.1  776  0  117  4.3  36  8.3  91  3.3          Spain  799  1.6  581  0.3  104  5.8  38  10.5  76  1.3          Germany  466  1.1  341  0  70  2.9  31  9.7  24  0          Greece  357  12.6  220  2.0  94  38  9  22.2  34  5.9          Italy  320  11.9  219  7.0  40  30.0  16  12.5  45  28.9          Switzerland  303  0.7  228  0.9  47  0  17  0  11  0          Turkey  294  23.8  172  8.0  103  48.5  14  42.9  5  0          The Netherlands  279  2.5  173  0  48  8.3  24  12.5  34  0          Portugal  230  10  145  5.0  69  23.2  0  0  16  0          Poland  217  4.6  159  2.0  33  15.2  7  14.3  18  5.6          Austria  137  0.7  105  0  16  0  8  12.5  8  0          Belgium  117  1.7  84  0  12  0  12  16.7  9  0        1998−2002  Asia Pacific      3655  5.9  1738  17.3  250  6.8  338  3.3  587  16  Bell (2003),    Australia      1311  0.5  328  3.7  130  0.8  151  0  178  4  Hirakata (2005)    China      163  24.5  75  30.7  10  30.0  9  0  38  37      Hong Kong      608  14.3  224  11.6  10  0  37  8.1  36  6      Japan      337  2.4  210  10.0  51  5.9  27  3.7  101  3      Philippines      338  5.0  319  21.9  13  38.5  33  0  94  35      Singapore      318  11.3  225  35.6  3  33.3  39  17.9  27  44      South Africa      261  1.5  135  28.1  16  0  27  0  54  20      Taiwan      319  5.6  222  13.5  17  23.5  15  0  59  19    1997−1999  Western Pacific      1104  7.9  560  24.6      111  1.8      Winokur (2001)    Europe      3822  5.3  946  22.6      442  11.1          Latin America      2026  8.5  897  45.4      196  22.4          United States      4966  3.3  2017  7.6      589  4.9          Canada      1203  4.2  368  4.9      97  3.1        2004  North America      1429  4.5                  Deshpande (2006)  *Data for E. cloacae isolates are from Bell (2003). View Large Table 1 Percentage of organisms expressing an ESBL phenotype in the SENTRY Antimicrobial Surveillance Program for various regions and countries in the past decade     No. of isolates tested and rate (%) of isolates with an ESBL phenotype        Total  Escherichia coli  Klebsiella pneumoniae  Klebsiella oxytoca  Proteus mirabilis  Enterobacter cloacae  Year(s) of study  Region Country  No.  %  No.  %  No.  %  No.  %  No.  %  No.  %  References  1997–1998  Europe  4707  4.9  3325  1.3  767  18.1  215  12.6  400  5.3      Nijssen (2004)    France  1020  1.1  776  0  117  4.3  36  8.3  91  3.3          Spain  799  1.6  581  0.3  104  5.8  38  10.5  76  1.3          Germany  466  1.1  341  0  70  2.9  31  9.7  24  0          Greece  357  12.6  220  2.0  94  38  9  22.2  34  5.9          Italy  320  11.9  219  7.0  40  30.0  16  12.5  45  28.9          Switzerland  303  0.7  228  0.9  47  0  17  0  11  0          Turkey  294  23.8  172  8.0  103  48.5  14  42.9  5  0          The Netherlands  279  2.5  173  0  48  8.3  24  12.5  34  0          Portugal  230  10  145  5.0  69  23.2  0  0  16  0          Poland  217  4.6  159  2.0  33  15.2  7  14.3  18  5.6          Austria  137  0.7  105  0  16  0  8  12.5  8  0          Belgium  117  1.7  84  0  12  0  12  16.7  9  0        1998−2002  Asia Pacific      3655  5.9  1738  17.3  250  6.8  338  3.3  587  16  Bell (2003),    Australia      1311  0.5  328  3.7  130  0.8  151  0  178  4  Hirakata (2005)    China      163  24.5  75  30.7  10  30.0  9  0  38  37      Hong Kong      608  14.3  224  11.6  10  0  37  8.1  36  6      Japan      337  2.4  210  10.0  51  5.9  27  3.7  101  3      Philippines      338  5.0  319  21.9  13  38.5  33  0  94  35      Singapore      318  11.3  225  35.6  3  33.3  39  17.9  27  44      South Africa      261  1.5  135  28.1  16  0  27  0  54  20      Taiwan      319  5.6  222  13.5  17  23.5  15  0  59  19    1997−1999  Western Pacific      1104  7.9  560  24.6      111  1.8      Winokur (2001)    Europe      3822  5.3  946  22.6      442  11.1          Latin America      2026  8.5  897  45.4      196  22.4          United States      4966  3.3  2017  7.6      589  4.9          Canada      1203  4.2  368  4.9      97  3.1        2004  North America      1429  4.5                  Deshpande (2006)      No. of isolates tested and rate (%) of isolates with an ESBL phenotype        Total  Escherichia coli  Klebsiella pneumoniae  Klebsiella oxytoca  Proteus mirabilis  Enterobacter cloacae  Year(s) of study  Region Country  No.  %  No.  %  No.  %  No.  %  No.  %  No.  %  References  1997–1998  Europe  4707  4.9  3325  1.3  767  18.1  215  12.6  400  5.3      Nijssen (2004)    France  1020  1.1  776  0  117  4.3  36  8.3  91  3.3          Spain  799  1.6  581  0.3  104  5.8  38  10.5  76  1.3          Germany  466  1.1  341  0  70  2.9  31  9.7  24  0          Greece  357  12.6  220  2.0  94  38  9  22.2  34  5.9          Italy  320  11.9  219  7.0  40  30.0  16  12.5  45  28.9          Switzerland  303  0.7  228  0.9  47  0  17  0  11  0          Turkey  294  23.8  172  8.0  103  48.5  14  42.9  5  0          The Netherlands  279  2.5  173  0  48  8.3  24  12.5  34  0          Portugal  230  10  145  5.0  69  23.2  0  0  16  0          Poland  217  4.6  159  2.0  33  15.2  7  14.3  18  5.6          Austria  137  0.7  105  0  16  0  8  12.5  8  0          Belgium  117  1.7  84  0  12  0  12  16.7  9  0        1998−2002  Asia Pacific      3655  5.9  1738  17.3  250  6.8  338  3.3  587  16  Bell (2003),    Australia      1311  0.5  328  3.7  130  0.8  151  0  178  4  Hirakata (2005)    China      163  24.5  75  30.7  10  30.0  9  0  38  37      Hong Kong      608  14.3  224  11.6  10  0  37  8.1  36  6      Japan      337  2.4  210  10.0  51  5.9  27  3.7  101  3      Philippines      338  5.0  319  21.9  13  38.5  33  0  94  35      Singapore      318  11.3  225  35.6  3  33.3  39  17.9  27  44      South Africa      261  1.5  135  28.1  16  0  27  0  54  20      Taiwan      319  5.6  222  13.5  17  23.5  15  0  59  19    1997−1999  Western Pacific      1104  7.9  560  24.6      111  1.8      Winokur (2001)    Europe      3822  5.3  946  22.6      442  11.1          Latin America      2026  8.5  897  45.4      196  22.4          United States      4966  3.3  2017  7.6      589  4.9          Canada      1203  4.2  368  4.9      97  3.1        2004  North America      1429  4.5                  Deshpande (2006)  *Data for E. cloacae isolates are from Bell (2003). View Large Large-scale surveillance, specifically on the prevalence of plasmid-mediated AmpC β-lactamases among Gram-negative bacteria, has not been well described until recently. From a batch of 752 isolates collected over a wide geographic area in the United States, plasmids encoding AmpC-type β-lactamases were found in K. pneumoniae (8.5%), K. oxytoca (6.9%), and E. coli (4%), and 20 of the 70 collection sites in 10 of the 25 states were involved (Alvarez et al, 2004). AmpC-mediated resistance was found in only nine clinical isolates of Salmonella from a large collection of 278 ;308 Salmonella isolates recovered from humans during the period 1992−2003 in England and Wales (Batchelor et al, 2005). Transmission from animal to humans Antimicrobial resistance occurs in several ways, respectively or concurrently. Pre-existing susceptible bacteria could become resistant through horizontal gene transfer originating from other resistant bacteria. Resistant bacteria could be selected under antimicrobial pressure from a heterogenous population already existing in the host. A susceptible host could acquire resistant bacteria from exogenous sources during antimicrobial therapy. For extended-spectrum cephalosporinases, the characteristic of being plasmid-mediated provides an efficient mechanism for the transmission of resistance. Actually, many epidemiological reports have demonstrated that common conjugative resistance plasmids as well as the same resistant clones can be found simultaneously from food animals and humans, suggesting that transmission of extended-spectrum cephalosporin resistance between animals and humans does occur (Weill et al, 2004; Yan et al, 2004; Bertrand et al, 2006). The transmission can also cross bacterial species borders, and, moreover, bacteria can spread these resistance determinants across animal species and their environment and further affect humans through various cryptic routes yet to be elucidated. Clinical studies have indicated that in vivo transmission of ceftriaxone resistance among members of the family Enterobacteriaceae could occur during antimicrobial therapy in patients (Su et al, 2003). Using a turkey model, a recent report demonstrated that a blaCMY-2-carrying conjugative plasmid could be transferred from donor E. coli to Salmonella enterica serotype Newport and then further to another serotype of E. coli in the gut (Poppe et al, 2005). Furthermore, during an outbreak investigation, the same clonal group of multidrug-resistant E. coli was recovered from clinical samples of hospitalized dogs with extraintestinal infections and from rectal swabs of staff working in a veterinary hospital (Sidjabat et al, 2006). A large field study demonstrated that the patterns of antimicrobial resistance were similar among isolates from faecal samples of farm animals, regardless of the animal species, and farm environment samples, which were considered to be related to surface-water contamination with antimicrobial resistant bacteria (Sayah et al, 2005). The resistant determinants may subsequently enter human bodies through water consumption and affect the therapeutic value of the associated antimicrobial agents when they are applied. Many human antibiotics or their analogues have been used for therapeutic purposes in veterinary medicine and as growth promoters in animal feed (Shryock, 2000). Increasing numbers of reports have indicated that this practice may contribute greatly to the increase of antimicrobial resistance in human pathogens through the food chain and that it should therefore be prohibited (Barton, 1998; Witte, 1998). Mechanisms of plasmid transfer A number of reports have indicated that genes encoding SHV (Haeggman et al, 1997), CTX-M (Decousser et al, 2001; Humeniuk et al, 2002; Poirel et al, 2002), and AmpC β-lactamases (Walther-Rasmussen & Høiby, 2002) were derived from chromosomal β-lactamase genes of certain bacterial species. The subsequent horizontal transfer of plasmids encoding these genes that occurred not just between organisms of the same species but also, in some cases, between quite distantly related species is the major cause of the rapid dissemination of resistance to β-lactam antibiotics. Mechanisms for the transfer of such resistance genes can be assigned to three categories: (1) conjugation of self-transmissible plasmids, genomic islands or elements (Pembroke & Murphy, 2000); (2) mobilization of a coexisting but physically independent plasmid consisting of an oriT (origin of transfer) sequence for DNA processing by a coresident self-transmissible plasmid; and (3) transfer of a cointegrate formed by the fusion of a conjugative element to another plasmid or to the bacterial chromosome. In general, classification of plasmids is based on their replication mechanisms in each incompatibility group (Shapiro, 1977; Lawley et al, 2004), and a PCR-based typing method will be discussed in the next section. To accomplish conjugation, conjugative plasmids posses some transfer-related functions, including an exclusion system located on the bacterial surface to avoid the redundant transfer between organisms with the same or related plasmids (Harrison et al, 1992), and randomly dispersed conjugative pili on the bacterial surface to provide one organism with multiple junctions with the neighboring organisms (Lawley et al, 2002). During mating, bacteria form aggregates, and the genetic elements then unwind, nick, and transport to the recipient organism (Wilkens & Lanka, 1993). However, some plasmids may not be able to conjugate, but they may be mobilized. Mobilizable plasmids consist of their own nic or oriT sites and proteins for recognition and cleavage, but the direction of the complex to the transferosome is determined by other conjugative elements. The majority of plasmid-encoded ESBL and AmpC genes are located on conjugative plasmids (Walther-Rasmussen & Høiby, 2002; 2004; Rupp & Fey, 2003; Liu et al, 2007; Wu et al, 2007). Only a few of these genes are found on nonself-transmissible plasmids, but such plasmids may be mobilizable (Winokur et al, 2000; Chiu et al, 2004; Liebana et al, 2004). The resistance genes are usually associated with insertion sequences (IS) and transposons. The class 1 integron-associated ORF, orf513, has been shown to be involved in the mobilization of several classes of resistance genes, including plasmid-encoded ampC and blaCTX-M genes (Arduino et al, 2002; 2003; Weill et al, 2004; Verdet et al, 2006; Wachino et al, 2006). Among class 1 integrons, a group of similar genetic elements, termed common regions (CRs), are usually found beyond but close to their 3′ conserved sequences. CRs demonstrate IS91-like features, which mobilize adjacent DNA through an atypical transposition mechanism termed rolling circle replication (Toleman et al, 2006a). They were thus considered as transferable elements and renamed ‘insertion sequence CRs’ (ISCRs) (Toleman et al, 2006a; b). The element orf513 was incorporated in the first CR element to be discovered, which was reported in the early 1990s as a DNA sequence of 2154 ;bp embedded in the complex class 1 integrons In6 and In7 (Stokes et al, 1993). The orf513-associated CR was thus called ISCR1 and has since been linked to various resistance genes (Toleman et al, 2006a; b). One interesting finding is that ISCR1 has thus far not been associated with the CMY-2 subgroup genes, which are invariably linked to ISEcp1 (Toleman et al, 2006b). ISEcp1 is also frequently associated with resistant isolates that express plasmid-mediated CTX-M- or AmpC-type β-lactamases (Chiu et al, 2004; Giles et al, 2004; Lartigue et al, 2004; Eckert et al, 2006; Su et al, 2006; Liu et al, 2007; Wu et al, 2007). Plasmid-encoded CTX-M-type ESBLs have been shown to originate from chromosomal cephalosporinases of Kluyvera spp. (Decousser et al, 2001; Humeniuk et al, 2002; Poirel et al, 2002), and ISEcp1 appears to play a key role in mediating such an evolutional change (Bonnet, 2004). Although the mechanism associated with ISEcp1 transposition is not fully understood, a closely related insertion sequence, ISEcp1B, has been shown to recognize a variety of similar nucleotide sequences as the right inverted repeat during a mobilization process and to lead to the insertion of ISEcp1B at various sites (Poirel et al, 2005). It is possible that ISEcp1 functions through a similar mechanism and results in the formation of a diverse genetic environment surrounding various plasmid-borne CTX-M-type β-lactamase genes (Lartigue et al, 2004; Eckert et al, 2006; Liu et al, 2007). In addition, typical −35 and −10 promoter sequences have been found to be located within the ISEcp1B upstream of a blaCTX-M-19 gene in a K. pneumoniae clinical isolate (Poirel et al, 2003) and within another ISEcp1-like element in front of a blaCMY-7 gene in a S. enterica serotype Typhimurium strain (Hossain et al, 2004). Thus, ISEcp1 or its derivatives may be responsible not only for the mobilization of plasmid-mediated CTX-M- and AmpC-type β-lactamase genes but also for their expression, a phenomenon that explains the frequent association of ISEcp1 with the two types of resistance genes. In contrast to the diverse genetic environment found in CTX-M-type genes, however, a number of reports from different geographic areas all indicated that a conserved DNA fragment consisting of a specific ISEcp1-blaCMY-2-blc-sugE structure is distributed among various Salmonella serotypes and several members of the family Enterobacteriaceae (Chiu et al, 2004; Giles et al, 2004; Su et al, 2006; Su & Chiu, 2007; Wu et al, 2007). A hypothesis was thus generated that the blaCMY-2 gene may have been disseminated among various genomic backgrounds through the transfer of plasmids containing such a conserved DNA fragment, rather than the resistance gene itself having been moved to separate plasmids or chromosomes (Giles et al, 2004; Su et al, 2006). Furthermore, the conserved genetic structure surrounding the blaCMY-2 gene has been described in a blaCMY-5-carrying plasmid from K. oxytoca, although the flanking regions beyond the structure were not explored (Wu et al, 1999; Giles et al, 2004). Based on the similarity between this conserved structure and the genetic organizations flanking the chromosomal ampC gene of C. freundii, it was postulated that plasmid-mediated CMY-type β-lactamase genes may originate from the chromosomal ampC gene of C. freundii (Wu et al, 1999). Although the role of these cotransferred genes in cephalosporin resistance remains unclear, the possible functions of blc (an outer membrane lipoprotein) and sugE (a member of the small multidrug resistance gene family encoding multidrug efflux proteins) indicate that they may be associated with multidrug resistance (Chung & Saier, 2002; Campanacci et al, 2006). Furthermore, the majority of this conserved genetic structure was found inserted into the same region of a finQ gene (Chiu et al, 2004; Su et al, 2006), which is a fertility inhibition gene of the F plasmid (Ham & Skurray, 1989). It is possible that disruption of the finQ gene may break its fertility inhibition function and presumptively could restore the conjugation ability of the plasmid itself. Whether or not it is through such an efficient mechanism that the blaCMY-2 gene is able to propagate and become relatively more prevalent than other ampC genes is a question that requires further study. Table 2 lists the four plasmids, encoding either blaCTX-M or blaCMY-2, the complete nucleotide sequences of which have been fully analysed. These β-lactamase genes are all linked to the ISEcp1, and the plasmids invariably belong to the IncI1 or IncI1-like incompatibility group (Table 2). Generally, the conjugation systems of the plasmids coevolve with their replicons, as conjugative plasmids of a given incompatibility group usually share similar, if not identical, transfer systems. This phenomenon suggests that the plasmids encoding extended-spectrum cephalosporinases may have evolved to be well adapted to the intracellular environment, along with a property of easy dissemination among various species of Enterobacteriaceae. Table 2 Genetic features of four fully sequenced plasmids encoding blaCTX Mor blaCMY 2 Species  Gene  Plasmid size (bp)  Incompatibility group  β Lactamase linked genes  Accession number  Reference  Citrobacter freundii  blaCTX M 3  89 468  IncI1 like plasmid  ISEcp1  NC_004464 AF550415  Boyd et al., (2004)  Escherichia coli  blaCTX M 15  92 353  IncFII (R100) plasmid  ISEcp1  NC_005327    Salmonella enterica serotype Choleraesuis  blaCMY 2  138 742  IncI1 (R64) like plasmid  ISEcp1blaCMY 2blc sugE  AY509004  Chiu et al., (2005)  Salmonella enterica  blaCMY 2  99 331  IncI1 (ColIB P9) like plasmid  ISEcp1blaCMY 2blc sugE  DQ017661    Species  Gene  Plasmid size (bp)  Incompatibility group  β Lactamase linked genes  Accession number  Reference  Citrobacter freundii  blaCTX M 3  89 468  IncI1 like plasmid  ISEcp1  NC_004464 AF550415  Boyd et al., (2004)  Escherichia coli  blaCTX M 15  92 353  IncFII (R100) plasmid  ISEcp1  NC_005327    Salmonella enterica serotype Choleraesuis  blaCMY 2  138 742  IncI1 (R64) like plasmid  ISEcp1blaCMY 2blc sugE  AY509004  Chiu et al., (2005)  Salmonella enterica  blaCMY 2  99 331  IncI1 (ColIB P9) like plasmid  ISEcp1blaCMY 2blc sugE  DQ017661    View Large Table 2 Genetic features of four fully sequenced plasmids encoding blaCTX Mor blaCMY 2 Species  Gene  Plasmid size (bp)  Incompatibility group  β Lactamase linked genes  Accession number  Reference  Citrobacter freundii  blaCTX M 3  89 468  IncI1 like plasmid  ISEcp1  NC_004464 AF550415  Boyd et al., (2004)  Escherichia coli  blaCTX M 15  92 353  IncFII (R100) plasmid  ISEcp1  NC_005327    Salmonella enterica serotype Choleraesuis  blaCMY 2  138 742  IncI1 (R64) like plasmid  ISEcp1blaCMY 2blc sugE  AY509004  Chiu et al., (2005)  Salmonella enterica  blaCMY 2  99 331  IncI1 (ColIB P9) like plasmid  ISEcp1blaCMY 2blc sugE  DQ017661    Species  Gene  Plasmid size (bp)  Incompatibility group  β Lactamase linked genes  Accession number  Reference  Citrobacter freundii  blaCTX M 3  89 468  IncI1 like plasmid  ISEcp1  NC_004464 AF550415  Boyd et al., (2004)  Escherichia coli  blaCTX M 15  92 353  IncFII (R100) plasmid  ISEcp1  NC_005327    Salmonella enterica serotype Choleraesuis  blaCMY 2  138 742  IncI1 (R64) like plasmid  ISEcp1blaCMY 2blc sugE  AY509004  Chiu et al., (2005)  Salmonella enterica  blaCMY 2  99 331  IncI1 (ColIB P9) like plasmid  ISEcp1blaCMY 2blc sugE  DQ017661    View Large Recent reports also indicate that a variety of widely disseminated conjugative plasmids are associated with the spread of CTX-M- and Amp-C-type enzymes. Some of the plasmids belong to the so-called broad-host-range plasmid groups, such as IncN (Carattoli et al, 2006; Hopkins et al, 2006; Novais et al, 2007), IncP1-α (Novais et al, 2006), IncL/M (Novais et al, 2007), and IncA/C2 (Carattoli et al, 2006; Novais et al, 2007), and thus their further spread to other members of Enterobacteriaceae and other bacterial species is a cause for concern. Replicon typing of plasmids that carry genes conferring resistance to extended-spectrum cephalosporins Plasmids with the same replication machinery cannot be propagated together, and therefore can be classified in incompatibility groups (Datta & Hughes, 1983; Couturier et al, 1988). Methods for determining incompatibility groups described in earlier reports involved conjugation/transformation and hybridization experiments (Datta & Hedges, 1971; Couturier et al, 1988) and were quite laborious and time-consuming. Recently a PCR-based replicon typing method was developed that allowed the rapid identification of major plasmid incompatibility groups among Enterobacteriaceae, i.e. FIA, FIB, FIC, HI1, HI2, I1-Iγ, N, P, W, T, A/C, K, B/O, X, Y, F, and FIIA (Carattoli et al, 2005). This PCR-based method has been used to monitor the dissemination and evolution of resistance plasmids, in particular those conferring resistance to extended-spectrum cephalosporins. Thus, in E. coli and Salmonella, CMY-2-type A and CMY-2-type B plasmids have been shown to belong to the A/C2 and I1 incompatibility groups, respectively (Carattoli et al, 2006; Hopkins et al, 2006). These plasmids have spread in the United States and in Europe. Depending on the blaCTX-M gene, different CTX-M plasmids have recently been identified and found to be of the I1, FII, HI2, K, and N incompatibility groups (Hopkins et al, 2006). These results demonstrate the association of certain β-lactamase genes with specific plasmid backbones. Very recently, the dissemination and persistence of blaCTX-M-9 were shown to be linked to CR1-containing class 1 integrons linked to defective transposon derivatives from Tn402 located in old antibiotic resistance plasmids of the HI2, P1-α, and FI incompatibility groups (Novais et al, 2006). It was suggested that the presence of this ESBL gene on broad-host-range IncP1-α plasmids might contribute to its dissemination to hosts that are not members of the family Enterobacteriaceae. Laboratory detection The rapid and accurate identification of organisms that express resistance to extended-spectrum cephalosporins among clinical isolates is a prerequisite for an effective antimicrobial therapy and the prevention of their further spread. The problem associated with the detection of such organisms is that they may appear susceptible to cephalosporins in in vitro phenotypic screening of antimicrobial susceptibility using conventional breakpoints (Paterson & Bonomo, 2005). Reports have documented that failure rates are unacceptably high when cephalosporins are used in the treatment of serious infections caused by organisms able to produce ESBLs or AmpC-type enzymes (Paterson et al, 2001; Pai et al, 2004), even with the evidence of in vitro susceptibility. One explanation for such clinical failure is that the extended-spectrum cephalosporinases produced by the organisms are able to hydrolyze the agents in vivo. Another important factor is the inoculum effect for ESBL-producers, because the MICs of cephalosporins rise as the inoculum of ESBL-producing organisms increases (Thomson & Moland, 2001). Thus, for infection sites where higher concentrations of bacterial organisms are present (e.g. those involved in intra-abdominal abscesses and pneumonia), or that are difficult to reach with certain antimicrobial agents (e.g. those involved in endocarditis, meningitis, and osteomyelitis), clinical failure of cephalosporin therapy would be expected even if the serum levels of antibiotics far exceeded the MIC of the antibiotic when tested in vitro at the conventional inoculum of 105 ;CFU ;mL−1. In view of these problems, the Clinical and Laboratory Standards Institute (CLSI, formerly the National Committee for Clinical Laboratory Standards) has recommended that ESBL production should be screened for E. coli, K. pneumoniae, K. oxytoca, and Proteusmirabilis (CLSI, 2006). A standard disk diffusion method, or alternatively a dilution method, has been proposed by the CLSI for screening ESBL-producing bacteria. Suspected ESBL-producing strains are selected and subjected to further phenotypic confirmatory tests (CLSI, 2006). According to the CLSI guideline, isolates with a positive phenotypic confirmatory test should be reported as resistant to all penicillins, cephalosporins (including cefepime, but excluding cephamycins), and monobactams, no matter what the original susceptibility of the particular agent is (CLSI, 2006). However, false identification of ESBLs has been reported for isolates expressing only non-ESBL β-lactamases as a result of the concurrent outer membrane protein deficiency or mutations in the promoter sequence (Rice et al, 2000; Wu et al, 2001). Some of these studies, although not all, indicated that successful treatment can be achieved with the use of third-generation cephalosporins (Wu et al, 2001). On the other hand, false-negative detection may also occur if the test isolate produces both ESBLs and AmpC-type β-lactamases, probably because the latter enzymes are resistant to the inhibition by clavulanate and hence mask the synergistic effect of cephalosporins and clavulanate against ESBLs (Steward et al, 2001). Currently there are no CLSI-recommended tests for detecting AmpC-type β-lactamases. However, several phenotypic methods for the screening of AmpC-type β-lactamases have been reported, including the three-dimensional test (Manchanda & Singh, 2003), the cefoxitin-agar method (Nasim et al, 2004), the Hodge test (Yong et al, 2002), and the double-disk test with various inhibitors or inducers to AmpC enzymes (Coudron, 2005; Dunne & Hardin, 2005). A recently reported new method, the AmpC disk test, using filter-paper disks impregnated with EDTA to detect the presence of plasmid-mediated AmpC-type β-lactamases, appears to represent a sensitive, specific, and convenient method for the detection of plasmid-mediated AmpC-type β-lactamases in organisms lacking a chromosomally mediated AmpC enzyme (Black et al, 2005). A multiplex PCR method for the detection of plasmid-meditated AmpC β-lactamases has also been devised (Pérez-Pérez & Hanson, 2002). Molecular methods for the identification of ESBL genes, such as blaSHVs and blaTEMs, usually involve amplification and sequencing of the target genes. For the much more diverse blaCTX-Ms, various primer pairs are required to amplify the target genes from various groups of CTX-M genes. The subsequent sequencing analysis then leads to the identification of the corresponding CTX-M genes. As clinical isolates are frequently associated with multiple resistance genes, the PCR/sequencing strategy described here appears simple but time-consuming. A novel system, which comprises a dual strategy that first uses multiplex PCR to detect blaSHVs, blaCTX-M-3-like and blaCTX-M-14-like genes, and then a modified SHV melting-curve mutation detection method to rapidly differentiate six blaSHV genes (blaSHV-1, blaSHV-2, blaSHV-2a, blaSHV-5, blaSHV-11, and blaSHV-12), has been developed (Chia et al, 2005). The system was designed to detect simultaneously the predominant ESBL genes in the local area where the study was conducted. For other areas, where different ESBLs are prevalent, the system can be easily modified to suit the individual situations. Antimicrobial therapy Considering the high prevalance of extended-spectrum cephalosporinase-producing strains among Enterobacteriaceae, selection of empirical antimicrobial therapy for infections caused by these bacteria should take into account the possibility that the isolate is an ESBL-producer. The judgment could be based on local susceptibility patterns of the individual bacteria species. Risk factors for infection with an ESBL-producing strain, including known colonization with an ESBL-producing organism, prolonged hospital stay, accommodation in an intensive care unit or other hospital area where ESBL-producers are known to be endemic, the use of invasive medical devices (e.g. urinary catheters, endotracheal tubes, central venous lines, etc.) for a prolonged period, and the use of various antibiotic classes, including quinolones, trimethoprim-sulfamethoxazole, aminoglycosides, metronidazole, and third-generation cephalosporins (Graffunder et al, 2005; Kanafani et al, 2005; Paterson & Bonomo, 2005), should also be considered. Critically ill patients with nosocomial K. pneumoniae or E. coli infections should probably be treated with antibiotics active against ESBL-producers until the absence of an ESBL is definitively established. As mentioned earlier, the use of cephalosporins to treat serious infections caused by ESBL-producers is associated with high rates of treatment failure, even in cases that the in vitro susceptibility has been clearly demonstrated (Paterson et al, 2001). Regarding cephamycins (for example cefoxitin, cefotetan, and flomoxef), although the agents are not liable to hydrolysis by ESBLs, clinical experience with their use in the treatment of ESBL-producing enterobacterial infections is limited (Paterson et al, 2001). A recent report indicated that flomoxef might have potential therapeutic effects in treating infections caused by ESBL-producing organisms (Lee et al, 2006). However, similar to the results described in early reports regarding the emerging resistance during therapy with cefoxitin (Pangon et al, 1989) or cefotetan (Bradford et al, 1997), collateral damage of prolonged flomoxef therapy could occur and lead to full resistance to flomoxef and ertapenem and reduced susceptibility to imipenem (Lee et al, 2007a). The resistance was attributable to the acquisition of a plasmid-mediated blaDHA-1 gene and the depletion of OmpK36 production in an original OmpK35-deficient, ESBL-producing K. pneumoniae isolate after flomoxef treatment (Lee et al, 2007a). Carbapenems are the treatment of choice for infections caused by AmpC- and ESBL-producing Enterobacteriaceae (Paterson, 2000; Paterson & Bonomo, 2005). Recently, a large prospective, multi-country study of K. pneumoniae bacteremia demonstrated that mortality in patients with infection caused by ESBL-producing K. pneumoniae was significantly lower when a carbapenem was used compared with other drug classes (Paterson et al, 2004). The greatest published experience has been with imipenem, but MICs for meropenem are only slightly lower than that for imipenem (Paterson et al, 2000). These two antibiotics may be interchangeable in the treatment of ESBL-producing enterobacterial infections. There is no published clinical experience with ertapenem. However, if an isolate is susceptible in vitro to ertapenem, it appears reasonable to use ertapenem for the treatment of the infection. Carbapenem resistance in Gram-negative bacteria could, however, occur through the production of carbapenem-hydrolyzing β-lactamases (Walsh et al, 2005), including serine carbapenemases (class A) (Lomaestro et al, 2006), metallo-β-lactamases (class B) (Yan et al, 2001), and oxacillinases (class D) (Poirel et al, 2004). Expression of plasmid-mediated class C β-lactamases (Bradford et al, 1997; Cao et al, 2000; Bidet et al, 2005; Kaczmarek et al, 2006; Lee et al, 2007a; b) or ESBLs (Crowley et al, 2002; Elliott et al, 2006; Mena et al, 2006; Kim et al, 2007) paralleling membrane impermeability has also been shown to confer carbapenem resistance. Caution must be exercised in the use of cefepime, a fourth-generation cephalosporin, in infections caused by AmpC-producing organisms. Novel AmpC-type β-lactamases conferring resistance to this antibiotic have been increasingly reported (Wachino et al, 2006). Treatment failure resulting from the emergence of resistance to cefepime itself or from the acquisition of other ESBL genes by the isolate, possibly during therapy, has also been reported (Song et al, 2005). In addition, cefepime is less reliable for therapy in cases of high-inoculum infections (Kang et al, 2004). Fluoroquinolones should be regarded as the second-line therapy for patients with K. pneumoniae bacteremia that may result from an ESBL-producer (Paterson, 2000). It should be noted that the probability of fluoroquinolone resistance is greater in isolates that are ESBL-producing than in those that are not (Paterson et al, 2000). Combinations of β-lactam/β-lactamase inhibitors may appear active in vitro against ESBL-producing K. pneumoniae but are subject to rising MICs as the inoculum of infecting organisms rises (Thomson & Moland, 2001), leading to clinical failures (Pillay et al, 1998). On the other hand, if other classes of antibiotics are to be selected as alternative therapeutic agents, antimicrobial susceptibility testing for these agents should be determined before use. Conclusions The high prevalence of clinical isolates producing plasmid-mediated extended-spectrum cephalosporinases is an epidemic of plasmids, which has generated serious therapeutic problems. The treatment of infections in hospitalized patients caused by these resistant bacteria is and will remain an important medical problem. It is likely that resistance among various Enterobacteriaceae to extended-spectrum cephalosporins will continue to increase owing to the wide dissemination of the resistance plasmids. This situation gives strong testimony to the resilience of microorganisms and their ability to adapt to their environment, such that the rate of increase of resistance will largely depend on the antimicrobial regimens in use. The ability to treat infections caused by these resistant organisms successfully demands a multifaceted approach combining continued research into and development of novel classes of antimicrobial agents, more prudent use of existing agents, and an emphasis on more effective infection control measures. Acknowledgements The work performed in Chang Gung Memorial Hospital and Chang Gung Children's Hospital on antimicrobial resistance in Enterobacteriaceae is in part supported by grants NSC95-2314-B-182A-025 from the National Science Council, Executive Yuan, Taiwan, and CMRPG350021 from Chang Gung Memorial Hospital, Taiwan. References Alvarez M. Tran J.H. Chow N. Jacoby G.A. ( 2004) Epidemiology of conjugative plasmid-mediated AmpC β-lactamases in the United States. Antimicrob Agents Chemother  48: 533– 537. Google Scholar CrossRef Search ADS PubMed  Arduino S.M. Roy P.H. Jacoby G.A. Orman B.E. Pineiro S.A. Centron D. ( 2002) blaCTX-M-2 is located in an unusual class 1 integron (In35) which includes Orf513. Antimicrob Agents Chemother  46: 2303– 2306. Google Scholar CrossRef Search ADS PubMed  Arduino S.M. Catalano M. Orman B.E. Roy P.H. Centron D. ( 2003) Molecular epidemiology of Orf513-bearing class 1 integrons in multiresistant clinical isolates from Argentinean hospitals. Antimicrob Agents Chemother  47: 3945– 3949. Google Scholar CrossRef Search ADS PubMed  Bae I.K. Lee Y.N. Jeong S.H. Hong S.G. Lee J.H. Lee S.H. Kim H.J. Youn H. ( 2007) Genetic and biochemical characterization of GES-5, an extended-spectrum class A beta-lactamase from Klebsiella pneumoniae. Diagn Microbiol Infect Dis  58: 465– 468. Google Scholar CrossRef Search ADS PubMed  Barton M.D. ( 1998) Does the use of antibiotics in animals affect human health? Aust Vet J  76: 177– 180. Google Scholar CrossRef Search ADS PubMed  Batchelor M. Hopkins K.L. Threlfall E.J. Clifton-Hadley F.A. Stallwood A.D. Davies R.H. Liebana E. ( 2005) Characterization of AmpC-mediated resistance in clinical Salmonella isolates recovered from humans during the period 1992 to 2003 in England and Wales. J Clin Microbiol  43: 2261– 2265. Google Scholar CrossRef Search ADS PubMed  Bauernfeind A. Grimm H. Schweighart S. ( 1990) A new plasmidic cefotaximase in a clinical isolate of Escherichia coli. Infection  18: 294– 298. Google Scholar CrossRef Search ADS PubMed  Bauernfeind A. Casellas J.M. Goldberg M. Holley M. Jungwirth R. Mangold P. Rohnisch T. Schweighart S. Wilhelm R. ( 1992) A new plasmidic cefotaximase from patients infected with Salmonella typhimurium. Infection  20: 158– 163. Google Scholar CrossRef Search ADS PubMed  Bauernfeind A. Stemplinger I. Jungwirth R. Mangold P. Amann S. Akalin E. An O. Bal C. Casellas J.M. ( 1996) Characterization of β-lactamase gene blaPER-2, which encodes an extended-spectrum class A β-lactamase. Antimicrob Agents Chemother  40: 616– 620. Google Scholar PubMed  Bell J.M. Turnidge J.D. Jones R.N. ( 2003) Prevalence of extended-spectrum β-lactamase-producing Enterobacter cloacae in the Asia-Pacific region: results from the SENTRY Antimicrobial Surveillance Program, 1998 to 2001. Antimicrob Agents Chemother  47: 3989– 3993. Google Scholar CrossRef Search ADS PubMed  Bertrand S. Weill F.X. Cloeckaert A. et al.   . ( 2006) Clonal emergence of extended-spectrum β-lactamase (CTX-M-2)-producing Salmonella enterica serovar Virchow isolates with reduced susceptibilities to ciprofloxacin among poultry and humans in Belgium and France (2000 to 2003). J Clin Microbiol  44: 2897– 2903. Google Scholar CrossRef Search ADS PubMed  Bidet P. Burghoffer B. Gautier V. Brahimi N. Mariani-Kurkdjian P. El-Ghoneimi A. Bingen E. Arlet G. ( 2005) In vivo transfer of plasmid-encoded ACC-1 AmpC from Klebsiella pneumoniae to Escherichia coli in an infant and selection of impermeability to imipenem in K. pneumoniae. Antimicrob Agents Chemother  49: 3562– 3565. Google Scholar CrossRef Search ADS PubMed  Black J.A. Moland E.S. Thomson K.S. ( 2005) AmpC disk test for detection of plasmid-mediated AmpC β-lactamases in Enterobacteriaceae lacking chromosomal AmpC β-lactamases. J Clin Microbiol  43: 3110– 3113. Google Scholar CrossRef Search ADS PubMed  Bonnet R. ( 2004) Growing group of extended-spectrum β-lactamases: the CTX-M enzymes. Antimicrob Agents Chemother  48: 1– 14. Google Scholar CrossRef Search ADS PubMed  Bonnet R. Sampaio JLM Chanal C. Sirot D. De Champs C. Viallard J.L. Labia R. Sirot J. ( 2000) A novel class A extended-spectrum β-lactamase (BES-1) in Serratia marcescens isolated in Brazil. Antimicrob Agents Chemother  44: 3061– 3068. Google Scholar CrossRef Search ADS PubMed  Boyd D.A. Tyler S. Christianson S. McGeer A. Muller M.P. Willey B.M. Bryce E. Gardam M. Nordmann P. Mulvey M.R. ( 2004) Complete nucleotide sequence of a 92-kilobase plasmid harboring the CTX-M-15 extended-spectrum β-lactamase involved in an outbreak in long-term-care facilities in Toronto, Canada. Antimicrob Agents Chemother  48: 3758– 3764. Google Scholar CrossRef Search ADS PubMed  Bradford P.A. ( 2001) Extended-spectrum β-lactamases in the 21st Century: characterization, epidemiology, and detection of this important resistance threat. Clin Microbiol Rev  14: 933– 951. Google Scholar CrossRef Search ADS PubMed  Bradford P.A. Urban C. Mariano N. Projan S.J. Rahal J.J. Bush K. ( 1997) Imipenem resistance in Klebsiella pneumoniae is associated with the combination of ACT-1, a plasmid-mediated AmpC β-lactamase, and the loss of an outer membrane protein. Antimicrob Agents Chemother  41: 563– 569. Google Scholar PubMed  Bush K. Jacoby G.A. Medeiros A.A. ( 1995) A functional classification scheme for β-lactamases and its correlation with molecular structure. Antimicrob Agents Chemother  39: 1211– 1233. Google Scholar CrossRef Search ADS PubMed  Campanacci V. Bishop R.E. Blangy S. Tegoni M. Cambillau C. ( 2006) The membrane bound bacterial lipocalin Blc is a functional dimer with binding preference for lysophospholipids. FEBS Lett  580: 4877– 4883. Google Scholar CrossRef Search ADS PubMed  Cao VTB Arlet G. Ericsson B.M. Tammelin A. Courvalin P. Lambert T. ( 2000) Emergence of imipenem resistance in Klebsiella pneumoniae owing to combination of plasmid-mediated CMY-4 and permeability alteration. J Antimicrob Chemother  46: 895– 900. Google Scholar CrossRef Search ADS PubMed  Carattoli A. Bertini A. Vila L. Falbo V. Hopkins K.L. Threlfall E.J. ( 2005) Identification of plasmids by PCR-based replicon typing. J Microbiol Methods  63: 219– 228. Google Scholar CrossRef Search ADS PubMed  Carattoli A. Miriagou V. Bertini A. Loli A. Colinon C. Vila L. Whichard J.M. Rossolini G.M. ( 2006) Replicon typing of plasmids encoding resistance to newer β-lactams. Emerg Infect Dis  12: 1145– 1148. Google Scholar CrossRef Search ADS PubMed  Caroff N. Espaze E. Gautreau D. Richetb H. Reynauda A. ( 2000) Analysis of the effects of -42 and -32 ampC promoter mutations in clinical isolates of Escherichia coli hyperproducing AmpC. J Antimicrob Chemother  45: 783– 788. Google Scholar CrossRef Search ADS PubMed  Chia J.H. Chu C. Su L.H. Chiu C.H. Kuo A.J. Sun C.F. Wu T.L. ( 2005) Development of a multiplex PCR and SHV melting-curve mutation detection system for detection of some SHV and CTX-M β-lactamases of Escherichia coli, Klebsiella pneumoniae, and Enterobactercloacae in Taiwan. J Clin Microbiol  43: 4486– 4491. Google Scholar CrossRef Search ADS PubMed  Chiu C.H. Su L.H. Chu C. Chia J.H. Wu T.L. Lin T.Y. Lee Y.S. Ou J.T. ( 2004) Isolation of Salmonella enterica serotype choleraesuis resistant to ceftriaxone and ciprofloxacin. Lancet  363: 1285– 1286. Google Scholar CrossRef Search ADS PubMed  Chiu C.H. Tang P. Chu C. Hu S. Bao Q. Yu J. Chou Y.Y. Wang H.S. Lee Y.S. ( 2005) The genome sequence of Salmonella enterica serovar Choleraesuis, a highly invasive and resistant zoonotic pathogen. Nucleic Acids Res  33: 1690– 1698. Google Scholar CrossRef Search ADS PubMed  Chung Y.J. Saier M.H. Jr ( 2002) Overexpression of the Escherichia colisugE gene confers resistance to a narrow range of quaternary ammonium compounds. J Bacteriol  184: 2543– 2545. Google Scholar CrossRef Search ADS PubMed  Clinical and Laboratory Standards Institute ( 2006) Performance standards for antimicrobial susceptibility testing, 16th informational supplement (M100–S16) . CLSI, Wayne, PA. Coudron P.E. ( 2005) Inhibitor-based methods for detection of plasmid-mediated AmpC β-lactamases in Klebsiella spp., Escherichia coli, and Proteus mirabilis. J Clin Microbiol  43: 4163– 4167. Google Scholar CrossRef Search ADS PubMed  Couturier M. Bex F. Bergquist P.L. Maas W.K. ( 1988) Identification and classification of bacterial plasmids. Microbiol Rev  52: 375– 395. Google Scholar PubMed  Crowley B. Benedi V.J. Domenech-Sanchez A. ( 2002) Expression of SHV-2 β-lactamase and of reduced amounts of OmpK36 porin in Klebsiella pneumoniae results in increased resistance to cephalosporins and carbapenems. Antimicrob Agents Chemother  46: 3679– 3682. Google Scholar CrossRef Search ADS PubMed  Datta N. Hedges R.W. ( 1971) Compatibility groups among fi-R factors. Nature (London)  234: 222– 223. Google Scholar CrossRef Search ADS   Datta N. Hughes V.M. ( 1983) Plasmids of the same Inc groups in Enterobacteria before and after the medical use of antibiotics. Nature  306: 616– 617. Google Scholar CrossRef Search ADS PubMed  Datta N. Kontomichalou P. ( 1965) Penicillinase synthesis controlled by infectious R factors in Enterobacteriaceae. Nature  208: 239– 241. Google Scholar CrossRef Search ADS PubMed  Decousser J.W. Poirel L. Nordmann P. ( 2001) Characterization of a chromosomally encoded extended-spectrum class A β-lactamase from Kluyvera cryocrescens. Antimicrob Agents Chemother  45: 3595– 3598. Google Scholar CrossRef Search ADS PubMed  Deshpande L.M. Jones R.N. Fritsche T.R. Sader H.S. ( 2006) Occurrence of plasmidic AmpC type β-lactamase-mediated resistance in Escherichia coli: report from the SENTRY Antimicrobial Surveillance Program (North America, 2004). Int J Antimicrob Agents  28: 578– 581. Google Scholar CrossRef Search ADS PubMed  Du Bois S.K. Marriott M.S. Amyes S.G. ( 1995) TEM- and SHV-derived extended-spectrum β-lactamases: relationship between selection, structure and function. J Antimicrob Chemother  35: 7– 22. Google Scholar CrossRef Search ADS PubMed  Dunne W.M. Jr Hardin D.J. ( 2005) Use of several inducer and substrate antibiotic combinations in a disk approximation assay format to screen for AmpC induction in patient isolates of Pseudomonas aeruginosa, Enterobacter spp., Citrobacter spp., and Serratia spp. Clin Microbiol  43: 5945– 5949. Google Scholar CrossRef Search ADS   Eckert C. Gautier V. Arlet G. ( 2006) DNA sequence analysis of the genetic environment of various blaCTX-M genes. J Antimicrob Chemother  57: 14– 23. Google Scholar CrossRef Search ADS PubMed  Elliott E. Brink A.J. Van Greune J. Els Z. Woodford N. Turton J. Warner M. Livermore D.M. ( 2006) In vivo development of ertapenem resistance in a patient with pneumonia caused by Klebsiella pneumoniae with an extended-spectrum β-lactamase. Clin Infect Dis  42: e95– e98. Google Scholar CrossRef Search ADS PubMed  Giles W.P. Benson A.K. Olson M.E. Hutkins R.W. Whichard J.M. Winokur P.L. Fey P.D. ( 2004) DNA sequence analysis of regions surrounding blaCMY-2 from multiple Salmonella plasmid backbones. Antimicrob Agents Chemother  48: 2845– 2852. Google Scholar CrossRef Search ADS PubMed  Girlich D. Poirel L. Leelaporn A. Karim A. Tribuddharat C. Fennewald M. Nordmann P. ( 2001) Molecular epidemiology of the integron-located VEB-1 extended-spectrum beta-lactamase in nosocomial enterobacterial isolates in Bangkok, Thailand. J Clin Microbiol  39: 175– 182. Google Scholar CrossRef Search ADS PubMed  Graffunder E.M. Preston K.E. Evans A.M. Venezia R.A. ( 2005) Risk factors associated with extended-spectrum β-lactamase-producing organisms at a tertiary care hospital. J Antimicrob Chemother  56: 139– 145. Google Scholar CrossRef Search ADS PubMed  Haeggman S. Löfdahl S. Burman L.G. ( 1997) An allelic variant of the chromosomal gene for class A β-lactamase K2, specific for Klebsiella pneumoniae, is the ancestor of SHV-1. Antimicrob Agents Chemother  41: 2705– 2709. Google Scholar PubMed  Ham L.M. Skurray R. ( 1989) Molecular analysis and nucleotide sequence of finQ, a transcriptional inhibitor of the F plasmid transfer genes. Mol Gen Genet  216: 99– 105. Google Scholar CrossRef Search ADS PubMed  Harrison J.L. Taylor I.M. Platt K. O'Connor C.D. ( 1992) Surface exclusion specificity of the TraT lipoprotein is determined by single alterations in a five-amino-acid region of the protein. Mol Microbiol  6: 2825– 2832. Google Scholar CrossRef Search ADS PubMed  Hirakata Y. Matsuda J. Miyazaki Y. et al.   . ( 2005) Regional variation in the prevalence of extended-spectrum β-lactamase-producing clinical isolates in the Asia-Pacific region (SENTRY 1998-2002). Diagn Microbiol Infect Dis  52: 323– 329. Google Scholar CrossRef Search ADS PubMed  Hopkins K.L. Liebana E. Villa L. Batchelor M. Threlfall E.J. Carratoli A. ( 2006) Replicon typing of plasmids carrying CTX-M or CMY β-lactamases circulating among Salmonella and Escherichia coli isolates. Antimicrob Agents Chemother  50: 3203– 3206. Google Scholar CrossRef Search ADS PubMed  Hossain A. Reisbig M.D. Hanson N.D. ( 2004) Plasmid-encoded functions compensate for the biological cost of AmpC overexpression in a clinical isolate of Salmonella typhimurium. J Antimicrob Chemother  53: 964– 970. Google Scholar CrossRef Search ADS PubMed  Huang I.F. Chiu C.H. Wang M.H. Wu C.Y. Hsieh K.S. Chiou C.C. ( 2005) Outbreak of dysentery associated with ceftriaxone-resistant Shigella sonnei: first report of plasmid-mediated CMY-2-type AmpC beta-lactamase resistance in S.sonnei. J Clin Microbiol  43: 2608– 2612. Google Scholar CrossRef Search ADS PubMed  Humeniuk C. Arlet G. Gautier V. Grimont P. Labia R. Philippon A. ( 2002) Beta-lactamases of Kluyvera ascorbata, probable progenitors of some plasmid-encoded CTX-M types. Antimicrob Agents Chemother  46: 3045– 3049. Google Scholar CrossRef Search ADS PubMed  Jacoby G.A. Medeiros A.A. ( 1991) More extended-spectrum β-lactamases. Antimicrob Agents Chemother  35: 1697– 1704. Google Scholar CrossRef Search ADS PubMed  Kaczmarek F.M. Dib-Hajj F. Shang W. Gootz T.D. ( 2006) High-level carbapenem resistance in a Klebsiella pneumoniae clinical isolate is due to the combination of blaACT-1β-lactamase production, porin OmpK35/36 insertional inactivation, and down-regulation of the phosphate transport porin PhoE. Antimicrob Agnets Chemother  50: 3396– 3406. Google Scholar CrossRef Search ADS   Kanafani Z.A. Mehio-Sibai A. Araj G.F. Kanaan M. Kanj S.S. ( 2005) Epidemiology and risk factors for extended-spectrum β-lactamase-producing organisms: a case control study at a tertiary care center in Lebanon. Am J Infect Control  33: 326– 332. Google Scholar CrossRef Search ADS PubMed  Kang C.I. Pai H. Kim S.H. Kim H.B. Kim E.C. Oh M.D. Choe K.W. ( 2004) Cefepime and the inoculum effect in tests with Klebsiella pneumoniae producing plasmid-mediated AmpC-type β-lactamase. J Antimicrob Chemother  54: 1130– 1133. Google Scholar CrossRef Search ADS PubMed  Kim S.Y. Park Y.J. Yu J.K. Kim H.S. Park Y.S. Yoon J.B. Yoo J.Y. Lee K. ( 2007) Prevalence and mechanisms of decreased susceptibility to carbapenems in Klebsiella pneumoniae isolates. Diagn Microbiol Infect Dis  57: 85– 91. Google Scholar CrossRef Search ADS PubMed  Kliebe C. Nies B.A. Meyer J.F. Tolxdorff-Neutzling R.M. Wiedemann B. ( 1985) Evolution of plasmid-coded resistance to broad-spectrum cephalosporins. Antimicrob Agents Chemother  28: 302– 307. Google Scholar CrossRef Search ADS PubMed  Lartigue M.F. Poirel L. Nordmann P. ( 2004) Diversity of genetic environment of the blaCTX-M genes. FEMS Microbiol Lett  234: 201– 207. Google Scholar CrossRef Search ADS PubMed  Lawley T. Wilkins B.M. Frost L.S. ( 2004) Bacterial conjugation in gram-negative bacteria. Plasmid Biology  ( Funnell B.E. Phillips G.J., eds), pp. 203– 226. ASM Press, Washington DC. Google Scholar CrossRef Search ADS   Lawley T.D. Gordon G.S. Wright A. Taylor D.E. ( 2002) Bacterial conjugative transfer: visualization of successful mating pairs and plasmid establishments in live Escherichia coli. Mol Microbiol  44: 947– 956. Google Scholar CrossRef Search ADS PubMed  Lee C.H. Su L.H. Tang Y.F. Liu J.W. ( 2006) Treatment of ESBL-producing Klebsiella pneumoniae bacteraemia with carbapenems or flomoxef: a retrospective study and laboratory analysis of the isolates. J Antimicrob Chemother  58: 1074– 1077. Google Scholar CrossRef Search ADS PubMed  Lee C.H. Chu C. Liu J.W. Chen Y.S. Chiu C.J. Su L.H. ( 2007a) Collateral damage of flomoxef therapy: in vivo development of porin deficiency and acquisition of blaDHA−1 leading to ertapenem resistance in a clinical isolate of Klebsiella pneumoniae producing CTX-M-3 and SHV-5 β-lactamases. J Antimicrob Chemother  60: 410– 413. Google Scholar CrossRef Search ADS   Lee K. Yong D. Choi Y.S. Yum J.H. Kim J.M. Woodford N. Livermore D.M. Chong Y. ( 2007b) Reduced imipenem susceptibility in Klebsiella pneumoniae clinical isolates with plasmid-mediated CMY-2 and DHA-1 β-lactamases co-mediated by porin loss. Int J Antimicrob Agents  29: 201– 206. Google Scholar CrossRef Search ADS   Liebana E. Gibbs M. Clouting C. et al.   . ( 2004) Characterization of beta-lactamases responsible for resistance to extended-spectrum cephalosporins in Escherichia coli and Salmonella enterica strains from food-producing animals in the United Kingdom. Microb Drug Resist  10: 1– 9. Google Scholar CrossRef Search ADS PubMed  Liu S.Y. Su L.H. Yeh Y.L. Chu C. Chen H.L. Chiu C.H. ( 2007) Molecular characterization of plasmids encoding the CTX-M-3 type extended-spectrum β-lactamase from Salmonella, Escherichia coli, and Klebsiella pneumoniae. Int J Antimicrob Agents  29: 440– 445. Google Scholar CrossRef Search ADS PubMed  Lomaestro B.M. Tobin E.H. Shang W. Gootz T. ( 2006) The spread of Klebsiella pneumoniae carbapenemase-producing K. pneumoniae to upstate New York. Clin Infect Dis  43: e26– e28. Google Scholar CrossRef Search ADS PubMed  Manchanda V. Singh N.P. ( 2003) Occurrence and detection of AmpC β-lactamases among gram-negative clinical isolates using a modified three-dimensional test at Guru Tegh Bahadur Hospital, Delhi, India. J Antimicrob Chemother  51: 415– 418. Google Scholar CrossRef Search ADS PubMed  Matsumoto Y. Inoue M. ( 1999) Characterization of SFO-1, a plasmid-mediated inducible class A β-lactamase from Enterobacter cloacae. Antimicrob Agents Chemother  43: 307– 313. Google Scholar PubMed  Matsumoto Y. Ikeda F. Kamimura T. Yokota Y. Mine Y. ( 1988) Novel plasmid-mediated β-lactamase from Escherichia coli that inactivates oxyimino-cephalosporins. Antimicrob Agents Chemother  32: 1243– 1246. Google Scholar CrossRef Search ADS PubMed  Mena A. Plasencia V. García L. Hidalgo O. Ayestarán J.I. Alberti S. Borrell N. Pérez J.L. Oliver A. ( 2006) Characterization of a large outbreak by CTX-M-1-producing Klebsiella pneumoniae and mechanisms leading to in vivo carbapenem resistance development. J Clin Microbiol  44: 2831– 2837. Google Scholar CrossRef Search ADS PubMed  Miriagou V. Tzouvelekis L.S. Villa L. Lebessi E. Vatopoulos A.C. Carattoli A. Tzelepi E. ( 2004) CMY-13, a novel inducible cephalosporinase encoded by an Escherichia coli plasmid. Antimicrob Agents Chemother  48: 3172– 3174. Google Scholar CrossRef Search ADS PubMed  Nakano R. Okamoto R. Nakano Y. Kaneko K. Okitsu N. Hosaka Y. Inoue M. ( 2004) CFE-1, a novel plasmid-encoded AmpC β-lactamase with an ampR gene originating from Citrobacter freundii. Antimicrob Agents Chemother  48: 1151– 1158. Google Scholar CrossRef Search ADS PubMed  Nasim K. Elsayed S. Pitout J.D. Conly J. Church D.L. Gregson D.B. ( 2004) New method for laboratory detection of AmpC β-lactamases in Escherichia coli and Klebsiella pneumoniae. J Clin Microbiol  42: 4799– 4802. Google Scholar CrossRef Search ADS PubMed  Nijssen S. Florijn A. Bonten M.J. Schmitz F.J. Verhoef J. Fluit A.C. ( 2004) β-Lactam susceptibilities and prevalence of ESBL-producing isolates among more than 5000 European Enterobacteriaceae isolates. Int J Antimicrob Agents  24: 585– 591. Google Scholar CrossRef Search ADS PubMed  Novais  Cantón R. Valverde A. Machado E. Galan J.C. Peixe L. Carattoli A. Baquero F. Coque T.M. ( 2006) Dissemination and persistence of blaCTX-M-9 are linked to class 1 integrons containing CR1 associated with defective transposon derivatives from Tn402 located in early antibiotic resistance plasmids of IncHI2, IncP1-α, and IncFI groups. Antimicrob Agents Chemother  50: 2741– 2750. Google Scholar CrossRef Search ADS PubMed  Novais  Cantón R. Moreira R. Peixe L. Baquero F. Coque Tm ( 2007) Emergence and dissemination of Enterobacteriaceae isolates producing CTX-M-1-like enzymes in Spain are associated with IncFII (CTX-M-15) and broad-host-range (CTX-M-1, -3, and -32) plasmids. Antimicrob Agents Chemother  51: 796– 799. Google Scholar CrossRef Search ADS PubMed  Pai H. Kang C.I. Byeon J.H. Lee K.D. Park W.B. Kim H.B. Kim E.C. Oh M.D. Choe K.W. ( 2004) Epidemiology and clinical features of bloodstream infections caused by AmpC-type β-lactamase-producing Klebsiella pneumoniae. Antimicrob Agents Chemother  48: 3720– 3728. Google Scholar CrossRef Search ADS PubMed  Pangon B. Bizet C. Bure A. Pichon F. Philippon A. Regnier B. Gutmann L. ( 1989) In vivo selection of a cephamycin-resistant, porin-deficient mutant of Klebsiella pneumoniae producing a TEM-3 beta-lactamase. J Infect Dis  159: 1005– 1006. Google Scholar CrossRef Search ADS PubMed  Paterson D.L. ( 2000) Recommendations for treatment of severe infections caused by Enterobacteriaceae producing extended-spectrum β-lactamases (ESBLs). Clin Microbiol Infect  6: 460– 463. Google Scholar CrossRef Search ADS PubMed  Paterson D.L. Bonomo R.A. ( 2005) Extended-spectrum β-lactamases: a clinical update. Clin Microbiol Rev  18: 657– 686. Google Scholar CrossRef Search ADS PubMed  Paterson D.L. Mulazimoglu L. Casellas J.M. et al.   . ( 2000) Epidemiology of ciprofloxacin resistance and its relationship to extended-spectrum β-lactamase production in Klebsiella pneumoniae isolates causing bacteremia. Clin Infect Dis  30: 473– 478. Google Scholar CrossRef Search ADS PubMed  Paterson D.L. Ko W.C. Von Gottberg A. Casellas J.M. Mulazimoglu L. Klugman K.P. Bonomo R.A. Rice L.B. McCormack J.G. Yu V.L. ( 2001) Outcome of cephalosporin treatment for serious infections due to apparently susceptible organisms producing extended-spectrum β-lactamases (ESBLs): implications for the clinical microbiology laboratory. J Clin Microbiol  39: 2206– 2212. Google Scholar CrossRef Search ADS PubMed  Paterson D.L. Ko W.C. Von Gottberg A. et al.   . ( 2004) Antibiotic therapy for Klebsiellapneumoniae bacteremia: implications of production of extended spectrum β-lactamase. Clin Infect Dis  39: 31– 37. Google Scholar CrossRef Search ADS PubMed  Pembroke J.T. Murphy D.B. ( 2000) Isolation and analysis of a circular form of the IncJ conjugative-like elements, R391 and R997: implications for IncJ incompatibility. FEMS Microbiol Lett  187: 133– 138. Google Scholar CrossRef Search ADS PubMed  Pérez-Pérez F.J. Hanson N.D. ( 2002) Detection of plasmid-mediated AmpC β-lactamase genes in clinical isolates by using multiplex PCR. J Clin Microbiol  40: 2153– 2162. Google Scholar CrossRef Search ADS PubMed  Perilli M. De Santis F. Mugnaioli C. Rossolini G.M. Luzzaro F. Stefani S. Mezzatesta M.L. Toniolo A. Amicosante G. ( 2007) Spread of Enterobacteriaceae carrying the PER-1 extended-spectrum beta-lactamase gene as a chromosomal insert: a report from Italy. J Antimicrob Chemother  59: 323– 324. Google Scholar CrossRef Search ADS PubMed  Philippon A. Arlet G. Jacoby G.A. ( 2002) Plasmid-determined AmpC-type β-lactamases. Antimicrob Agents Chemother  46: 1– 11. Google Scholar CrossRef Search ADS PubMed  Pillay T. Pillay D.G. Adhikari M. Sturm A.W. ( 1998) Piperacillin/tazobactam in the treatment of Klebsiella pneumoniae infections in neonates. Am J Perinatol  15: 47– 51. Google Scholar CrossRef Search ADS PubMed  Poirel L. Naas T. Guibert M. Chaibi E.B. Labia R. Nordmann P. ( 1999) Molecular and biochemical characterization of VEB-1, a novel class A extended-spectrum β-lactamase encoded by an Escherichia coli integron gene. Antimicrob Agents Chemother  43: 573– 581. Google Scholar PubMed  Poirel L. Le Thomas I. Naas T. Karim A. Nordmann P. ( 2000) Biochemical sequence analyses of GES-1, a novel class A extended-spectrum β-lactamase, and the class 1 integron In52 from Klebsiella pneumoniae. Antimicrob Agents Chemother  44: 622– 632. Google Scholar CrossRef Search ADS PubMed  Poirel L. Kampfer P. Nordmann P. ( 2002) Chromosome-encoded Ambler class A β-lactamase of Kluyvera georgiana, a probable progenitor of a subgroup of CTX-M extended-spectrum β-lactamases. Antimicrob Agents Chemother  46: 4038– 4040. Google Scholar CrossRef Search ADS PubMed  Poirel L. Decousser J.W. Nordmann P. ( 2003) Insertion sequence ISEcp1B is involved in the expression and mobilization of a blaCTX-Mβ-lactamase gene. Antimicrob Agents Chemother  47: 2938– 2945. Google Scholar CrossRef Search ADS PubMed  Poirel L. Hertitier C. Tolun V. Nordmann P. ( 2004) Emergence of oxacillinase-mediated resistance to imipenem in Klebsiella pneumoniae. Antimicrob Agents Chemother  48: 15– 22. Google Scholar CrossRef Search ADS PubMed  Poirel L. Lartigue M.F. Decousser J.W. Nordmann P. ( 2005) ISEcp1B-mediated transposition of blaCTX-M in Escherichia coli. Antimicrob Agents Chemother  49: 447– 450. Google Scholar CrossRef Search ADS PubMed  Poppe C. Martin L.C. Gyles C.L. Reid-Smith R. Boerlin P. McEwen S.A. Prescott J.F. Forward K.R. ( 2005) Acquisition of resistance to extended-spectrum cephalosporins by Salmonella enterica subsp. enterica serovar Newport and Escherichia coli in the turkey poult intestinal tract. Appl Environ Microbiol  71: 1184– 1192. Google Scholar CrossRef Search ADS PubMed  Reisbig M.D. Hanson N.D. ( 2002) The ACT-1 plasmid-encoded AmpC β-lactamase is inducible: detection in a complex β-lactamase background. J Antimicrob Chemother  49: 557– 560. Google Scholar CrossRef Search ADS PubMed  Rice L.B. Carias L.L. Hujer A.M. Bonafede M. Hutton R. Hoyen C. Bonomo R.A. ( 2000) High-level expression of chromosomally encoded SHV-1 β-lactamase and an outer membrane protein change confer resistance to ceftazidime and piperacillin-tazobactam in a clinical isolate of Klebsiella pneumoniae. Antimicrob Agents Chemother  44: 362– 367. Google Scholar CrossRef Search ADS PubMed  Rupp M.E. Fey P.D. ( 2003) Extended spectrum β-lactamase (ESBL)-producing Enterobacteriaceae. Drugs  63: 353– 365. Google Scholar CrossRef Search ADS PubMed  Sanders C.C. ( 1987) Chromosomal cephalosporinases responsible for multiple resistance to the newer β-lactam antibiotics. Annu Rev Microbiol  41: 573– 593. Google Scholar CrossRef Search ADS PubMed  Sayah R.S. Kaneene J.B. Johnson Y. Miller R. ( 2005) Patterns of antimicrobial resistance observed in Escherichia coli isolates obtained from domestic- and wild-animal fecal samples, human septage, and surface water. Appl Environ Microbiol  71: 1394– 1404. Google Scholar CrossRef Search ADS PubMed  Shapiro J.A. ( 1977) Bacterial plasmids. DNA Insertion Elements, Plasmids, and Episomes  ( Bukhari A.I. Shapiro J.A. Adhya S.L., eds), pp. 601– 670. Cold Spring Harbor Laboratory Press, New York. Shryock T.J. ( 2000) Growth promotion and feed antibiotics. Antimicrobial Therapy in Veterinary Epidemiology , 3rd edn ( Prescott J.F. Baggott J.D. Walker R.D., eds), pp. 735– 743. Iowa State University Press, Ames, IA. Sidjabat H.E. Townsend K.M. Lorentzen M. Gobius K.S. Fegan N. Chin JJC Bettelheim K.A. Hanson N.D. Bensink J.C. Trott D.J. ( 2006) Emergence and spread of two distinct clonal groups of multidrug-resistant Escherichia coli in a veterinary teaching hospital in Australia. J Med Microbiol  55: 1125– 1134. Google Scholar CrossRef Search ADS PubMed  Silva J. Aguilar C. Ayala G. Estrada M.A. Garza-Ramos U. Lara-Lemus R. Ledezma L. ( 2000) TLA-1: a new plasmid-mediated extended-spectrum beta-lactamase from Escherichia coli. Antimicrob Agents Chemother  44: 997– 1003. Google Scholar CrossRef Search ADS PubMed  Song W. Moland E.S. Hanson N.D. Lewis J.S. Jorgensen J.H. Thomson K.S. ( 2005) Failure of cefepime therapy in treatment of Klebsiella pneumoniae bacteremia. J Clin Microbiol  43: 4891– 4894. Google Scholar CrossRef Search ADS PubMed  Steward C.D. Rasheed J.K. Hubert S.K. et al.   . ( 2001) Characterization of clinical isolates of Klebsiella pneumoniae from 19 laboratories using the National Committee for Clinical Laboratory Standards extended-spectrum β-lactamase detection methods. J Clin Microbiol  39: 2864– 2872. Google Scholar CrossRef Search ADS PubMed  Stokes H.W. Tomaras C. Parsons Y. Hall R.M. ( 1993) The partial 30-conserved segment duplications in the integrons In6 from pSa and In7 from pDGO100 have a common origin. Plasmid  30: 39– 50. Google Scholar CrossRef Search ADS PubMed  Su L.H. Chiu C.H. ( 2007) Salmonella: clinical importance and evolution of nomenclature. Chang Gung Med J  30: 210– 219. Google Scholar PubMed  Su L.H. Chiu C.H. Chu C. Wang M.H. Chia J.H. Wu T.L. ( 2003) In-vivo acquisition of ceftriaxone resistance in Salmonella enterica serotype Anatum. Antimicrob Agents Chemother  47: 563– 567. Google Scholar CrossRef Search ADS PubMed  Su L.H. Wu T.L. Chia J.H. Chu C. Kuo A.J. Chiu C.H. ( 2005) Increasing ceftriaxone resistance in Salmonella isolates from a university hospital in Taiwan. J Antimicrob Chemother  55: 846– 852. Google Scholar CrossRef Search ADS PubMed  Su L.H. Chen H.L. Liu S.Y. Chu C. Chia J.H. Wu T.L. Chiu C.H. ( 2006) Distribution of a transposon-like element carrying blaCMY-2 among Salmonella and other Enterobacteriaceae. J Antimicrob Chemother  57: 424– 429. Google Scholar CrossRef Search ADS PubMed  Szczepanowski R. Krahn I. Linke B. Goesmann A. Pühler A. Schlüter A. ( 2004) Antibiotic multiresistance plasmid pRSB101 isolated from a wastewater treatment plant is related to plasmids residing in phytopathogenic bacteria and carries eight different resistance determinants including a multidrug transport system. Microbiology  150: 3613– 3630. Google Scholar CrossRef Search ADS PubMed  Thomson K.S. Moland E.S. ( 2001) Cefepime, piperacillin-tazobactam, and the inoculum effect in tests with extended-spectrum β-lactamase-producing Enterobacteriaceae. Antimicrob Agents Chemother  45: 3548– 3554. Google Scholar CrossRef Search ADS PubMed  Toleman M.A. Bennett P.M. Walsh T.R. ( 2006a) Common regions e.g. orf513 and antibiotic resistance: IS91-like elements evolving complex class 1 integrons. J Antimicrob Chemother  58: 1– 6. Google Scholar CrossRef Search ADS   Toleman M.A. Bennett P.M. Walsh T.R. ( 2006b) ISCR elements: novel gene-capturing systems of the 21st century. Microbiol Mol Biol Rev  70: 296– 316. Google Scholar CrossRef Search ADS   Turner P.J. ( 2004) Extended-spectrum β-lactamases. Clin Infect Dis  41: S273– S275. Google Scholar CrossRef Search ADS   Vahaboglu H. Hall L.M. Mulazimoglu L. Dodanli S. Yildirim I. Livermore D.M. ( 1995) Resistance to extended-spectrum cephalosporins, caused by PER-1 β-lactamase, in Salmonella typhimurium from Istanbul, Turkey. J Med Microbiol  43: 294– 299. Google Scholar CrossRef Search ADS PubMed  Verdet C. Benzerara Y. Gautier V. Adam O. Ould-Hocine Z. Arlet G. ( 2006) Emergence of DHA-1-producing Klebsiella spp. in the Parisian region: genetic organization of the ampC and ampR genes originating from Morganella morganii. Antimicrob Agents Chemother  50: 607– 617. Google Scholar CrossRef Search ADS PubMed  Vourli S. Tzouvelekis L.S. Tzelepi E. Kartali G. Kontopoulou C. Sofianou D. ( 2003) Characterization of Klebsiella pneumoniae clinical strains producing a rare extended-spectrum β-lactamase (IBC-1). Int J Antimicrob Agents  21: 495– 497. Google Scholar CrossRef Search ADS PubMed  Wachino J. Kurokawa H. Suzuki S. Yamane K. Shibata N. Kimura K. Ike Y. Arakawa Y. ( 2006) Horizontal transfer of blaCMY-bearing plasmids among clinical Escherichia coli and Klebsiella pneumoniae isolates and emergence of cefepime-hydrolyzing CMY-19. Antimicrob Agents Chemother  50: 534– 541. Google Scholar CrossRef Search ADS PubMed  Walsh T.R. Toleman M.A. Poirel L. Nordmann P. ( 2005) Metallo-β-lactamases: the quiet before the storm? Clin Microbiol Rev  18: 306– 325. Google Scholar CrossRef Search ADS PubMed  Walther-Rasmussen J. Høiby N. ( 2002) Plasmid-borne AmpC β-lactamases. Can J Microbiol  48: 479– 493. Google Scholar CrossRef Search ADS PubMed  Walther-Rasmussen J. Høiby N. ( 2004) Cefotaximases (CTX-M-ases), an expanding family of extended-spectrum β-lactamases. Can J Microbiol  50: 137– 165. Google Scholar CrossRef Search ADS PubMed  Weill F.X. Lailler R. Praud K. Kerouanton A. Fabre L. Brisabois A. Grimont P.A. Cloeckaert A. ( 2004) Emergence of extended-spectrum-β-lactamase (CTX-M-9)-producing multiresistant strains of Salmonella enterica serotype Virchow in poultry and humans in France. J Clin Microbiol  42: 5767– 5773. Google Scholar CrossRef Search ADS PubMed  Wilkens B. Lanka E. ( 1993) DNA processing and replication during plasmid transfer between gram-negative bacteria. Bacterial Conjugation  ( Clewell D.B., ed), pp. 105– 136. ASM Press, Washington DC. Google Scholar CrossRef Search ADS   Winokur P.L. Brueggemann A. DeSalvo D.L. Hoffmann L. Apley M.D. Uhlenhopp E.K. Pfaller M.A. Doern G.V. ( 2000) Animal and human multidrug-resistance, cephalosporin-resistasnt Salmonella isolates expressing a plasmid-mediated CMY-2 AmpC β-lactamase. Antimicrob Agents Chemother  44: 2777– 2783. Google Scholar CrossRef Search ADS PubMed  Winokur P.L. Canton R. Casellas J.M. Legakis N. ( 2001) Variations in the prevalence of strains expressing an extended-spectrum β-lactamase phenotype and characterization of isolates from Europe, the Americas, and the Western Pacific region. Clin Infect Dis  32 2, S94– S103. Google Scholar CrossRef Search ADS PubMed  Witte W. ( 1998) Medical consequences of antibiotic use in agriculture. Science  279: 996– 997. Google Scholar CrossRef Search ADS PubMed  Wu S.W. Dornbusch K. Kronvall G. Norgren M. ( 1999) Characterization and nucleotide sequence of a Klebsiella oxytoca cryptic plasmid encoding a CMY-type β-lactamase: confirmation that the plasmid-mediated cephamycinase originated from the Citrobacter freundii AmpC β-lactamase. Antimicrob Agents Chemother  43: 1350– 1357. Google Scholar PubMed  Wu T.L. Siu L.K. Su L.H. Lauderdale T.L. Leu H.S. Lin T.Y. Ho M. ( 2001) Outer membrane protein change combined with co-existing TEM-1 and SHV-1 β-lactamases lead to false identification of ESBL-producing Klebsiella pneumoniae. J Antimicrob Chemother  47: 755– 761. Google Scholar CrossRef Search ADS PubMed  Wu T.L. Chia J.H. Su L.H. Chiu C.H. Kuo A.J. Ma Ling Siu L.K. ( 2007) CMY-2 β-lactamase-carrying community-acquired urinary tract Escherichia coli: genetic correlation with Salmonella enterica serotypes Choleraesuis and Typhimurium. Int J Antimicrob Agents  29: 410– 416. Google Scholar CrossRef Search ADS PubMed  Yan J.J. Ko W.C. Tasi S.H. Wu H.M. Wu J.J. ( 2001) Outbreak of infection with multidrug-resistant Klebsiella pneumoniae carrying blaIMP-8 in a university medical center in Taiwan. J Clin Microbiol  39: 4433– 4439. Google Scholar CrossRef Search ADS PubMed  Yan J.J. Hong C.Y. Ko W.C. Chen Y.J. Tsai S.H. Chuang C.L. Wu J.J. ( 2004) Dissemination of blaCMY-2 among Escherichia coli isolates from food animals, retail ground meats, and humans in southern Taiwan. Antimicrob Agents Chemother  48: 1353– 1356. Google Scholar CrossRef Search ADS PubMed  Yong D. Park R. Yum J.H. Lee K. Choi E.C. Chong Y. ( 2002) Further modification of the Hodge test to screen AmpC β-lactamase (CMY-1)-producing strains of Escherichia coli and Klebsiella pneumoniae. J Microbiol Methods  51: 407– 410. Google Scholar CrossRef Search ADS PubMed  © 2007 Federation of European Microbiological Societies
TI - An epidemic of plasmids? Dissemination of extended-spectrum cephalosporinases among Salmonella and other Enterobacteriaceae
JF - Journal of the Endocrine Society
DO - 10.1111/j.1574-695X.2007.00360.x
DA - 2008-03-01
UR - https://www.deepdyve.com/lp/oxford-university-press/an-epidemic-of-plasmids-dissemination-of-extended-spectrum-gsae4f0Zy0
SP - 155
EP - 168
VL - 52
IS - 2
DP - DeepDyve
ER -