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Drug Resistance Updates journal homepage: www.elsevier.com/locate/drup

Antimicrobial resistance among Enterobacteriaceae in South America: History, current dissemination status and associated socioeconomic factors Raquel Regina Bonelli, Beatriz Meurer Moreira, Renata Cristina Picão ∗ LIM Laboratório Integrado de Microbiologia, Instituto de Microbiologia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil

a r t i c l e Keywords: Enterobacteria Carbapenemase ESBL qnr rmtD Health system Food Environment

i n f o

a b s t r a c t South America exhibits some of the higher rates of antimicrobial resistance in Enterobactericeae worldwide. This continent includes 12 independent countries with huge socioeconomic differences, where the ample access to antimicrobials, including counterfeit ones, coexists with ineffective health systems and sanitation problems, favoring the emergence and dissemination of resistant strains. This work presents a literature review concerning the evolution and current status of antimicrobial resistance threats found among Enterobacteriaceae in South America. Resistance to ␤-lactams, fluoroquinolones and aminoglycosides was emphasized along with description of key epidemiological studies that highlight the success of specific resistance determinants in different parts of the continent. In addition, a discussion regarding political and socioeconomic factors possibly related to the dissemination of antimicrobial resistant strains in clinical settings and at the community is presented. Finally, in order to assess the possible sources of resistant bacteria, we compile the current knowledge about the occurrence of antimicrobial resistance in isolates in South American’ food, food-producing animals and off-hospitals environments. By addressing that intensive intercontinental commerce and tourism neutralizes the protective effect of geographic barriers, we provide arguments reinforcing that globally integrated efforts are needed to decelerate the emergence and dissemination of antimicrobial resistant strains. © 2014 Elsevier Ltd. All rights reserved.

1. Introduction The rapid evolution and spread of antimicrobial-resistant bacteria in parallel with insufficient development of new active drugs seriously affect future anti-infective therapy of bacterial infections, especially those due to Gram-negative rods (Boucher et al., 2009). Experts in the field estimate that by the next decade the world will have witnessed the wide dissemination of untreatable (or next-to-untreatable) infections, both within and beyond hospitals (Grundmann et al., 2011). To avoid or at least attempt to retard this crisis, many researchers have dedicated their efforts to elucidate factors favoring the emergence and global spread of antimicrobialresistant bacteria. Developing countries are considered key actors in this scenario. Populations in subnormal agglomerates are often more susceptible to infections due to increased prevalence of underlying

∗ Corresponding author at: Av. Carlos Chagas Filho, 373 – Centro de Ciências da Saúde, Bloco I, Instituto de Microbiologia, Universidade Federal do Rio de Janeiro, Cidade Universitária, Rio de Janeiro, RJ 21941-902, Brazil. Tel.: +55 21 2560 8344; fax: +55 21 256083 44. E-mail address: [email protected] (R.C. Picão).

diseases and malnutrition. In addition, the intense crosstransmission of microorganisms in hospitals in conjunction with ineffective healthcare systems, insecure drug supply chains and inconsistent accessibility to newly developed drugs favor the occurrence and dissemination of antimicrobial-resistant infections in clinical settings (Franco-Paredes and Santos-Preciado, 2010; Isturiz and Carbon, 2000; Larson, 2007; Okeke, 2010; Planta, 2007). Moreover, the economy of many developing countries relies on agriculture and livestock keeping, activities known to use large amounts of antimicrobials to increase productivity. The immediate consequence of such practices is the selection of antimicrobialresistant bacteria within the animals’ microbiota and among soil and water courses (Capita and Alonso-Calleja, 2013; Mellon et al., 2001). Contaminated environments together with poor sanitation, crowded living conditions and unsafe drinking water supply, in turn, favor the spread of antimicrobial-resistant bacteria throughout the community. The features mentioned above together with the lack of financial resources and political will to address the problem disastrously made developing countries fertile lands for the evolution of antimicrobial resistance. South America includes 12 nations that altogether comprise approximately 400 million people, which represent nearly 6% of the world population. These countries have experienced rapid

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Please cite this article in press as: Bonelli, R.R., et al., Antimicrobial resistance among Enterobacteriaceae in South America: History, current dissemination status and associated socioeconomic factors. Drug Resist. Updat. (2014), http://dx.doi.org/10.1016/j.drup.2014.02.001

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economic growth over the last decade, reflected in increased human development indexes (HDI). In the last HDI rank, of 2012, Chile was the best positioned (40th position) South American country, followed by Argentina (45th), Uruguay (51st), Venezuela (71st), Peru (77th), Brazil (85th), Ecuador (89th), Colombia (91st), Suriname (105th), Bolivia (108th), Paraguay (111th) and Guyana (118th). Nevertheless, enormous income distribution disparities remain ensuing poor living conditions for a significant part of their population. More than 16 million people are estimated to experience multidimensional poverty in South America (UN, 2013). An additional meaningful index is the expenditures in public health expressed as a fraction of the Gross Domestic Product (GDP). The South American average (3.7%) was inferior to that of the World (6.5%), ranging from 1.7% (Venezuela) to 5.6% (Uruguay), with decreasing values from 2000 to 2010 for most South American countries. These data underline the lack of priority of public health in this region (The World Bank data). Antimicrobial resistance in South American countries has long been documented to be more intense than in developed ones (Gales et al., 2011; Jaimes, 2005; Marra et al., 2011; Rosenthal et al., 2010; Wolff, 1993). In this review, we attempted to describe a brief history and current status regarding the dissemination of key antimicrobial-resistant Enterobacteriaceae, throughout South America, vis-à-vis to factors that might have contributed to their emergence and dissemination in that region. 2. Antimicrobial resistance in Enterobacteriaceae from South American’s clinical settings Multidrug-resistant Enterobacteriaceae is a major concern in South America. These microorganisms play important roles as etiologic agents of both nosocomial and community-acquired infections, even in very remote societies (Bartoloni et al., 2009; Cuzon et al., 2013; Gales et al., 2012; Rocha et al., 2012; Villegas et al., 2011; Woerther et al., 2010). The following sections of this manuscript are dedicated to present an overview of resistance to ␤-lactams, fluoroquinolones, aminoglycosides, polymyxins and tigecycline in Enterobacteriaceae isolated in South America. Based on published data, the chronology of emergence of ␤-lactamases as well as fluoroquinolone and aminoglycoside resistance determinants found in Enterobacteriaceae recovered in South America was summarized in Table 1. 2.1. ˇ-Lactamase production: emergence timeline and dissemination status ␤-Lactamases have been classified according to their molecular characteristics and functional properties in schemes that have been continuously updated (Bush, 2013). Extended-spectrum cephalosporin and carbapenem hydrolyzing enzymes are especially important as these antimicrobials are extensively used to treat infections due to Gram-negative rods. In this section we describe the emergence and dissemination of the main families of extended-spectrum ␤-lactamases (ESBL), plasmid-mediated AmpC and carbapenemases in South America. 2.1.1. Extended-spectrum ˇ-lactamases and plasmid-mediated AmpC The first transferable ESBL, SHV-2, was described in 1983 from a Klebsiella ozaenae clinical isolate recovered in Germany (Kliebe et al., 1985; Knothe et al., 1983). Few years later, SHV-5 was reported in Klebsiella pneumoniae isolated in Chile (Gutmann et al., 1989). Although this constituted the first report on ESBL production in South America, posterior literature provided evidences that Klebsiella spp. producing transferable SHV enzymes had been circulating in Argentinean clinical settings since 1982 (Casellas and

Goldberg, 1989). The emergence of CTX-M-2 and PER-2 enzymes was also noticed in Argentina during the early 1990s, in Salmonella Typhimurium clinical isolates (Bauernfeind et al., 1992, 1996). Shortly after its first description, PER-2 was observed among Escherichia coli, K. pneumoniae and Proteus mirabilis in that country (Bauernfeind et al., 1996). Nonetheless, ESBL production was not restricted to Argentina. Different studies conducted with Enterobacteriaceae clinical isolates recovered during the 1990s showed a trend toward lower levels of cephalosporin susceptibility in Brazil, Colombia and Venezuela (Araque et al., 2000; Gales et al., 1997; Jones et al., 1997). While at that time this phenomenon was solely attributed to the production of TEM- and SHV-like ESBL in Venezuela, Brazil witnessed the first description of CTX-M-2 and CTX-M9 variants whereas in Argentina CTX-M-2 was already the most prevalent ESBL among different Enterobacteriaceae such as K. pneumoniae, E. coli, Enterobacter aerogenes, Enterobacter cloacae, Serratia marcescens, Shigella sonnei, Salmonella enterica, Morganella morganii, P. mirabilis and Providencia spp. (Bantar et al., 2000; Minarini et al., 2008a; Orman et al., 2002; Power et al., 1999; Quinteros et al., 2003; Radice et al., 2001). During the following years, in accordance with the international tendency, CTX-M enzymes became widespread, not only among inpatients and outpatients over the continent, but also among specimens obtained from healthy children living in Peru and Bolivia (Bonnet, 2004; Guzman and Alonso, 2009; Minarini et al., 2009; Naseer and Sundsfjord, 2011; Pallecchi et al., 2004; Tollentino et al., 2011). CTX-M variants described included mostly CTX-M-2 though other groups such as CTX-M-1, CTX-M-9 and CTX-M-8 were also identified in South American countries (Cergole-Novella et al., 2010; Minarini et al., 2009; Pallecchi et al., 2004, 2007; Pulido et al., 2011; Sennati et al., 2012; Villegas et al., 2004). The early success of CTX-M ESBLs as resistance determinants for oxyiminocephalosporins among communitary Enterobacteriaceae is well represented in a study performed with isolates obtained between 2000 and 2005 from outpatients obtained in a city located in Southeast Brazil. Among 257 isolates resistant to nalidixic acid, 24 (9.3%) showed a positive ESBL phenotype. Among these, the CTXM-2-like, CTX-M-9, CTX-M-8 and SHV-5 enzymes were identified in 13, 3, 2 and 6 isolates, respectively. This wide variety of ESBL enzymes were detected in different bacterial species, such as E. coli (n = 9), K. pneumoniae (n = 6), E. cloacae (n = 5), Providencia stuartii (n = 2), M. morganii (n = 1) and Citrobacter freundii (n = 1) (Minarini et al., 2009). In 2004, the occurrence of CTX-M-15, enzyme reported to hydrolyze ceftazidime more efficiently than other CTX-M variants, was reported for the first time in South America from an E. coli clinical isolate recovered in Peru (Pallecchi et al., 2004). Subsequently, CTX-M-15-producing E. coli were identified in clinical isolates from Bolivia and Brazil (Cergole-Novella et al., 2010; Pallecchi et al., 2007). In parallel, the incidence of CTX-M-15 among inpatients and outpatients in Argentina during 2010 reached about 40%, suggesting a shift from the predominance of CTX-M-2 producers (Sennati et al., 2012). Other ESBL families sparsely identified in Enterobacteriaceae from South America, more specifically in Brazil, comprised those belonging to the BES and GES family, including the GES-5 variant showing carbapenemase activity (Bonnet et al., 2000; Dropa et al., 2010; Picao et al., 2010). Although plasmid-mediated AmpC was first described in South America during the 1990s (FOX-1 in a K. pneumoniae clinical isolate from Argentina), the following report, a CMY-2 enzyme, occurred more than 10 years later, in K. pneumoniae and Citrobacter koserii coproducing CTX-M-2 (Gonzalez et al., 1994; Rapoport et al., 2008). Of notice, posterior studies evidenced that CMY became disseminated in South America during the 2000s, especially throughout the

Please cite this article in press as: Bonelli, R.R., et al., Antimicrobial resistance among Enterobacteriaceae in South America: History, current dissemination status and associated socioeconomic factors. Drug Resist. Updat. (2014), http://dx.doi.org/10.1016/j.drup.2014.02.001

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Table 1 Chronology of resistance mechanisms affecting ␤-lactams, fluoroquinolones and aminoglycosides in Enterobacteriacea from South America, according to the year of isolation. Mechanism ␤-Lactamase SHV ESBL FOX CTX-M-2-group PER BES CTX-M-9-group CTX-M-1-group CTX-M-8-group IMP TEM ESBL GES ESBL KPC-2 VIM CMY GES carbapenemase KPC-3 OXA-48 NDM Resistance to fluoroquinolones QnrB QnrA Aac(6 )Ib-cr QnrS

Year of isolation

Microorganism

Country

Reference

1987 1989 1990 1990 1996 2000 2002 2002 2003 2003 2004 2004 2005 2005 2005 2006 2008 2008 2008 2011

K. pneumoniae K. pneumoniae S. Typhimurium S. Typhimurium S. marcescens Klebsiella spp. E. coli K. pneumoniae E. coli K. pneumoniae K. pneumoniae K. pneumoniae K. pneumoniae K. pneumoniae K. pneumoniae S. flexneri K. pneumoniae K. pneumoniae K. pneumoniae K. pneumoniae

Chile Argentina Argentina Argentina Brazil Brazil Peru Colombia Brazil Brazil Brazil Brazil Colombia Brazil Venezuela Argentina Brazil Colombia Argentina Colombia

Gutmann et al., 1989 Leiza et al. (1994) Bauernfeind et al. (1992) Bauernfeind et al. (1996) Bonnet et al. (2000) Minarini et al. (2008a,b) Pallecchi et al. (2004) Villegas et al. (2004) Minarini et al. (2009) Lincopan et al. (2005) Dropa et al. (2010) Dropa et al. (2010) Villegas et al. (2006) Pavez et al. (2009) Marcano et al. (2008) Rapoport et al. (2008) Picao et al. (2010) Lopez et al. (2011) Arduino et al. (2012) Escobar-Perez et al. (2013)

2003 2005 2005 2005

C. freundii E. cloacae E. coli E. coli K. pneumoniae K. oxytoca K. pneumoniae

Brazil Brazil Peru Peru Peru Peru Bolivia

Minarini et al. (2008b) Minarini et al. (2007) Pallecchi et al. (2007) Pallecchi et al. (2009)

1998

E. cloacae C. freundii S. marcescens E. coli K. pneumoniae

Argentina Argentina Argentina Brazil Brazil

Tijet et al. (2011) Fritsche et al. (2008) Bueno et al. (2013)

Resistance to aminoglycosides RmtD RmtB RmtG

2005 2010

community. For instance, CMY was described in Shigella flexneri isolates recovered from bloody stool of Argentinean children (Rapoport et al., 2008). In Santiago, Chile, the prevalence of plasmid-mediated AmpC-producing P. mirabilis isolated from inand outpatients at a University Hospital increased from 0.17% to 4.5% between 2006 and 2009 (Trevino et al., 2012). The blaCMY-2 gene has also been detected in E. coli isolates from hospitalized and outpatients in Argentina as well as from community-acquired urinary tract infections in Colombia (Jure et al., 2011; Leal et al., 2013; Martinez et al., 2012). The ESBL and plasmid-mediated AmpC families detected to date throughout South America is depicted in Fig. 1A. Regardless of the ␤-lactamase involved, surveillance studies demonstrated that oxyiminocephalosporin resistant Enterobacteriaceae have become continuously more prevalent in South American hospitals, which led to massive use of carbapenems and the consequent emergence of carbapenem-resistant isolates (Fernandez-Canigia and Dowzicky, 2012; Hawser et al., 2012; Villegas et al., 2011). This phenotype has been attributed to the association of ESBL or AmpC-production together with porin loss, also noticed in South American countries, as well as to the acquisition of carbapenemases, the most successful mechanism for carbapenem resistance among Enterobacteriaceae (Correa et al., 2013; Cuzon et al., 2013; Gomez et al., 2011a; Melano et al., 2003; Pavez et al., 2008; Pereira et al., 2013). Indeed, a statistically significant trend for imipenem resistance among Brazilian and Argentinean K. pneumoniae isolates was recently demonstrated (Gales et al., 2012). 2.1.2. Carbapenemases Acquired carbapenemases inactivate virtually all ␤-lactams including carbapenems, antimicrobials that have been frequently

applied to treat nosocomial infections. These enzymes show wide structural diversity and are classified under Ambler’s classes A, B and D (Nordmann et al., 2011). KPC (K. pneumoniae carbapenemase) is the main Ambler’s class A carbapenemase found in South America. It was first reported in K. pneumoniae recovered in the USA during 2001 and was detected in South America 4 years later, in Colombia (Villegas et al., 2006; Yigit et al., 2001). Subsequent reports demonstrated that KPC-2-producing K. pneumoniae was also present in Brazil and Argentina since 2005 and 2006, respectively. (Pavez et al., 2009; Gomez et al., 2011b). These isolates successfully disseminated, becoming endemic in several Brazilian hospitals (Monteiro et al., 2009; Peirano et al., 2009; Pereira et al., 2013; Zavascki et al., 2010). More recently, the first KPC-producing isolate was reported in Chile, from a patient who came from Italy with a history of multiple hospitalizations (Cifuentes et al., 2012). Colombia witnessed the first South American outbreak of infections due to KPC-3 producing K. pneumoniae. The index patient had come from Israel for a liver transplantation and the major clone associated with this outbreak was indistinguishable from isolates previously described in that country (Lopez et al., 2011). Subsequent reports evidenced that the incidence of infections due to KPC producers in Colombia increased from