Extended-Spectrum -Lactamases: a Clinical Update

s of the International Congress of Chemotherapy, Birmingham, England, 1999). In 1989 an outbreak of multiresistant Salmonella enterica serovar Typhimurium infections occurred in 12 of 14 Argentinian provinces. From these isolates a new non-SHV, non-TEM ESBL named CTX-M-2 was identified (26, 28, 29, 333). Organisms with CTX-M-2 have spread throughout many parts of South America (333). Other CTX-M enzymes (CTX-M-8, -9, and -16) have been discovered in Brazil (44, 46). Curiously, TEM-type ESBLs have been very rarely reported from South America. As noted above, two novel non-TEM, non-SHV ESBLs have been recently reported from South America: GES-1, isolated from an infant previously hospitalized in French Guiana (320), and BES-1, from an ESBLproducing Serratia marcescens isolate from a hospital in Rio de Janeiro (45). ESBLs have been found in 30 to 60% of klebsiellae from intensive care units in Brazil, Colombia, and Venezuela (245, 281, 306, 307, 349, 350). Reports of ESBL-producing organisms also exist from Central America and the Caribbean Islands (84, 114, 146, 370, 371). Africa and the Middle East. Several outbreaks of infections with ESBL-producing Klebsiella have been reported from South Africa (93, 188, 310, 367), but no national surveillance figures have been published. However, it has been reported that 36.1% of Klebsiella pneumoniae isolates collected in a single South African hospital in 1998 and 1999 were ESBL producers (33). ESBLs have also been documented in Israel, Saudi Arabia, and a variety of North African countries (3, 25, 35, 36, 47, 122, 247, 272). Outbreaks of Klebsiella infections with strains resistant to third-generation cephalosporins have been reported in Nigeria and Kenya without documentation of ESBL production (5, 264). A novel CTX-M enzyme (CTX-M12) has been found in Kenya (190). Characterization of ESBLs from South Africa has revealed TEM and SHV types (especially SHV-2 and SHV-5) (160, 315). A nosocomial outbreak of infections with Pseudomonas aeruginosa, expressing GES-2 has been described in South Africa (326). Australia. The first ESBLs to be detected in Australia were isolated from a collection of gentamicin-resistant Klebsiella spp. collected between 1986 and 1988 from Perth (259). These were characterized as being of SHV derivation (260). In the last decade, ESBL-producing organisms have been detected in every state of Australia and in the Northern Territory (33, 121, 169, 348, 359). Outbreaks of infection have occurred in both adult and pediatric patients. Overall, it appears that the proportion of Klebsiella pneumoniae isolates which are ESBL producers in Australian hospitals is about 5% (33). Asia. In 1988, isolates of Klebsiella pneumoniae from China which contained SHV-2 were reported (181). Further reports of other SHV-2-producing organism in China occurred in 1994 (83). In reports comprising limited numbers of isolates collected in 1998 and 1999, 30.7% of Klebsiella pneumoniae isolates and 24.5% of Escherichia coli isolates were ESBL producers (33). In a major teaching hospital in Beijing, 27% of Escherichia coli and Klebsiella pneumoniae blood culture isolates collected from 1997 through 1999 were ESBL producers (116). Of isolates collected from Zhejiang Province, 34% of Escherichia coli isolates and 38.3% of Klebsiella pneumoniae isolates were ESBL producing (438). National surveys have indicated the presence of ESBLs in 5 to 8% of Escherichia coli isolates from Korea, Japan, Malaysia, 662 PATERSON AND BONOMO CLIN. MICROBIOL. REV. on O cber 6, 2017 by gest ht://cm rasm .rg/ D ow nladed fom and Singapore but 12 to 24% in Thailand, Taiwan, the Philippines, and Indonesia. Rates of ESBL production by Klebsiella pneumoniae have been as low as 5% in Japan (215, 427) and 20 to 50% elsewhere in Asia. However, there are clearly differences from hospital to hospital: it has been reported that a quarter of all Klebsiella pneumoniae isolates from a hospital in Japan in 1998 and 1999 were ESBL producers (33). ESBLs of the SHV-2, SHV-5, and SHV-12 lineage initially dominated in those studies in which genotypic characterization has been carried out (209). Newly described SHV-type ESBLs have recently been reported from Taiwan and Japan (82, 202). However, the appearance of CTX-M ESBLs in India (189, 318) and China (81, 414, 425), and more frequent reports of outbreaks of infection with CTX-M-type ESBLs in Japan (200, 226), Korea (284), and Taiwan (436), raise suspicions that these may indeed be the dominant ESBL types in Asia. Plasmid-mediated non-TEM, non-SHV ESBLs, showing homology to the chromosomal -lactamases of Klebsiella oxytoca (Toho-1 and Toho-2), have been detected in Japan (173, 227). A new non-TEM, non-SHV ESBL (VEB-1) has been reported from Thailand and Vietnam (141, 142, 266, 323). Molecular Epidemiology of Nosocomial Infections with ESBL-Producing Organisms More than 50 studies (describing in total more than 3,000 patients) have been published in peer-reviewed medical literature utilizing molecular typing methods in the study of the epidemiology of nosocomial infections with ESBL-producing organisms (295). More than 75% of the studies have addressed ESBL-producing infections with Klebsiella pneumoniae. The predilection of ESBLs for Klebsiella pneumoniae has never been clearly explained. It should be noted that the parent enzyme of TEM-type ESBLs, TEM-1, is widespread in many other species. More relevant, given the frequent finding of SHV-type ESBLs in Klebsiella pneumoniae, may be the increased frequency of SHV-1 in Klebsiella pneumoniae versus other species. Almost all non-ESBL-producing Klebsiella pneumoniae isolates have chromosomally mediated SHV-1 -lactamases (21). In contrast, fewer than 10% of ampicillin-resistant Escherichia coli isolates harbor SHV-1 (219). Many ESBL genes are on large plasmids; even prior to the advent of ESBLs, large multiresistance plasmids were more common in klebsiellae than Escherichia coli (219). Of importance may be the well-noted adaptation of klebsiellae to the hospital environment. Klebsiellae survive longer than other enteric bacteria on hands and environmental surfaces, facilitating cross-infection within hospitals (75). In 100% of the more than 50 studies previously mentioned, at least two patients were colonized or infected with genotypically similar strains, implying patient-to-patient transmission of the strain. A number of outbreaks have been decribed with dissemination of a single clone of genotypically identical organism (131, 132, 143, 273). Clones have been found to persist for more than 3 years (57). However, in many hospitals a more complex molecular epidemiologic picture has emerged (20). Recent reports have described the clonal dissemination of at least five different ESBL-producing Klebsiella strains in the same unit at the same time (128). Additionally, members of a single epidemic strain may carry different plasmids (carrying different ESBL genes) (128). Furthermore, genotypically nonrelated strains may produce the same ESBL due to plasmid transfer from species to species (38, 128). Finally, although the same ESBL may be prevalent in a particular unit of a hospital, they may be mediated by different plasmids (53). This may imply independent evolution via the effects of antibiotic pressure, or plasmid transfer from organism to organism. Intensive care units are often the epicenter of ESBL production in hospitals—in one large outbreak, more than 40% af all the hospital’s ESBL-producing organisms were from patients in intensive care units (147). As was noted in the preESBL era, neonatal intensive care units can also be a focus of infections with multiply resistant klebsiellae (6, 38, 121, 217, 348, 386, 387, 408). Intensive care units in tertiary referral hospitals may acquire patients already colonized with ESBLproducing organisms, thereby triggering an outbreak of infection (147, 363, 364). Transfer of genotypically related ESBLs from hospital to hospital within a single city (40, 256, 351, 439), from city to city (439), and from country to country (128, 147, 365, 439) has been documented. A notable clone has been an SHV-4-producing, serotype K-25 isolate of Klebsiella pneumoniae which has spread to multiple hospitals in France and Belgium (439). Another notable dissemination has been of a TEM-24-producing Enterobacter aerogenes clone in France, Spain, and Belgium (68, 108, 119). Intercontinental transfer has also been described (365). Although ESBL-producing organisms can be introduced into intensive care units, epidemics of infection from intensive care units to other parts of the hospital have been well documented to occur (37, 182, 363). Likewise, ESBLs may spontaneously evolve outside of the intensive care unit. Units noted to have been affected by outbreaks include neurosurgical (37), burns (339), renal (131), obstetrics and gynecology (132), hematology and oncology (163, 270), and geriatric units (149, 268). Nursing homes and chronic care facilities may also be a focus of infections with ESBL-producing organisms. In these settings, clonal spread has also been documented (54, 343, 419). Risk Factors for Colonization and Infection with