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Drug Resistance Updates

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ntimicrobial resistance among Enterobacteriaceae in South America:istory, current dissemination status and associated

ocioeconomic factors

aquel Regina Bonelli, Beatriz Meurer Moreira, Renata Cristina Picão ∗

IM Laboratório Integrado de Microbiologia, Instituto de Microbiologia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil

r t i c l e i n f o

eywords:nterobacteriaarbapenemaseSBLnrmtDealth systemoodnvironment

a b s t r a c t

South America exhibits some of the higher rates of antimicrobial resistance in Enterobactericeae world-wide. This continent includes 12 independent countries with huge socioeconomic differences, where theample access to antimicrobials, including counterfeit ones, coexists with ineffective health systems andsanitation problems, favoring the emergence and dissemination of resistant strains. This work presentsa literature review concerning the evolution and current status of antimicrobial resistance threats foundamong Enterobacteriaceae in South America. Resistance to �-lactams, fluoroquinolones and aminoglyco-sides was emphasized along with description of key epidemiological studies that highlight the successof specific resistance determinants in different parts of the continent. In addition, a discussion regardingpolitical 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 ofresistant bacteria, we compile the current knowledge about the occurrence of antimicrobial resistance inisolates in South American’ food, food-producing animals and off-hospitals environments. By addressingthat intensive intercontinental commerce and tourism neutralizes the protective effect of geographicbarriers, we provide arguments reinforcing that globally integrated efforts are needed to decelerate theemergence and dissemination of antimicrobial resistant strains.
. Introduction

The rapid evolution and spread of antimicrobial-resistant bacte-ia in parallel with insufficient development of new active drugseriously affect future anti-infective therapy of bacterial infections,specially those due to Gram-negative rods (Boucher et al., 2009).xperts in the field estimate that by the next decade the worldill have witnessed the wide dissemination of untreatable (orext-to-untreatable) infections, both within and beyond hospitalsGrundmann et al., 2011). To avoid or at least attempt to retard thisrisis, many researchers have dedicated their efforts to elucidateactors favoring the emergence and global spread of antimicrobial-esistant bacteria.

Please cite this article in press as: Bonelli, R.R., et al., Antimicrobial resistdissemination status and associated socioeconomic factors. Drug Resi

Developing countries are considered key actors in this sce-ario. Populations in subnormal agglomerates are often moreusceptible to infections due to increased prevalence of underlying

∗ Corresponding author at: Av. Carlos Chagas Filho, 373 – Centro de Ciências daaúde, Bloco I, Instituto de Microbiologia, Universidade Federal do Rio de Janeiro,idade Universitária, Rio de Janeiro, RJ 21941-902, Brazil. Tel.: +55 21 2560 8344;ax: +55 21 256083 44.

E-mail address: [email protected] (R.C. Picão).

368-7646/$ – see front matter © 2014 Elsevier Ltd. All rights reserved.ttp://dx.doi.org/10.1016/j.drup.2014.02.001

© 2014 Elsevier Ltd. All rights reserved.

diseases and malnutrition. In addition, the intense cross-transmission of microorganisms in hospitals in conjunction withineffective healthcare systems, insecure drug supply chains andinconsistent accessibility to newly developed drugs favor the occur-rence and dissemination of antimicrobial-resistant infections inclinical settings (Franco-Paredes and Santos-Preciado, 2010; Isturizand Carbon, 2000; Larson, 2007; Okeke, 2010; Planta, 2007).Moreover, the economy of many developing countries relies onagriculture and livestock keeping, activities known to use largeamounts of antimicrobials to increase productivity. The immediateconsequence of such practices is the selection of antimicrobial-resistant bacteria within the animals’ microbiota and among soiland 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, inturn, favor the spread of antimicrobial-resistant bacteria through-out the community. The features mentioned above together withthe lack of financial resources and political will to address the prob-lem disastrously made developing countries fertile lands for the

ance among Enterobacteriaceae in South America: History, currentst. Updat. (2014), http://dx.doi.org/10.1016/j.drup.2014.02.001

evolution of antimicrobial resistance.South America includes 12 nations that altogether comprise

approximately 400 million people, which represent nearly 6% ofthe world population. These countries have experienced rapid

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dx.doi.org/10.1016/j.drup.2014.02.001

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conomic growth over the last decade, reflected in increaseduman development indexes (HDI). In the last HDI rank, of 2012,hile was the best positioned (40th position) South Americanountry, followed by Argentina (45th), Uruguay (51st), Venezuela71st), Peru (77th), Brazil (85th), Ecuador (89th), Colombia (91st),uriname (105th), Bolivia (108th), Paraguay (111th) and Guyana118th). Nevertheless, enormous income distribution disparitiesemain ensuing poor living conditions for a significant part of theiropulation. More than 16 million people are estimated to experi-nce multidimensional poverty in South America (UN, 2013). Andditional meaningful index is the expenditures in public healthxpressed as a fraction of the Gross Domestic Product (GDP). Theouth American average (3.7%) was inferior to that of the World6.5%), ranging from 1.7% (Venezuela) to 5.6% (Uruguay), withecreasing values from 2000 to 2010 for most South Americanountries. These data underline the lack of priority of public healthn this region (The World Bank data).

Antimicrobial resistance in South American countries has longeen documented to be more intense than in developed ones (Galest al., 2011; Jaimes, 2005; Marra et al., 2011; Rosenthal et al.,010; Wolff, 1993). In this review, we attempted to describe arief history and current status regarding the dissemination ofey antimicrobial-resistant Enterobacteriaceae, throughout Southmerica, vis-à-vis to factors that might have contributed to theirmergence and dissemination in that region.

. Antimicrobial resistance in Enterobacteriaceae fromouth American’s clinical settings

Multidrug-resistant Enterobacteriaceae is a major concern inouth America. These microorganisms play important roles astiologic agents of both nosocomial and community-acquirednfections, even in very remote societies (Bartoloni et al., 2009;uzon et al., 2013; Gales et al., 2012; Rocha et al., 2012; Villegast al., 2011; Woerther et al., 2010). The following sections of thisanuscript are dedicated to present an overview of resistance

o �-lactams, fluoroquinolones, aminoglycosides, polymyxins andigecycline in Enterobacteriaceae isolated in South America. Basedn published data, the chronology of emergence of �-lactamasess well as fluoroquinolone and aminoglycoside resistance deter-inants found in Enterobacteriaceae recovered in South Americaas summarized in Table 1.

.1. ˇ-Lactamase production: emergence timeline andissemination status

�-Lactamases have been classified according to their molec-lar characteristics and functional properties in schemes thatave been continuously updated (Bush, 2013). Extended-spectrumephalosporin and carbapenem hydrolyzing enzymes are espe-ially important as these antimicrobials are extensively used toreat infections due to Gram-negative rods. In this section weescribe the emergence and dissemination of the main families ofxtended-spectrum �-lactamases (ESBL), plasmid-mediated AmpCnd carbapenemases in South America.

.1.1. Extended-spectrum ˇ-lactamases and plasmid-mediatedmpC

The first transferable ESBL, SHV-2, was described in 1983 from Klebsiella ozaenae clinical isolate recovered in Germany (Kliebet al., 1985; Knothe et al., 1983). Few years later, SHV-5 waseported in Klebsiella pneumoniae isolated in Chile (Gutmann et al.,


989). Although this constituted the first report on ESBL produc-ion in South America, posterior literature provided evidences thatlebsiella spp. producing transferable SHV enzymes had been cir-ulating in Argentinean clinical settings since 1982 (Casellas and

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Goldberg, 1989). The emergence of CTX-M-2 and PER-2 enzymeswas also noticed in Argentina during the early 1990s, in SalmonellaTyphimurium clinical isolates (Bauernfeind et al., 1992, 1996).Shortly after its first description, PER-2 was observed amongEscherichia 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 iso-lates recovered during the 1990s showed a trend toward lowerlevels of cephalosporin susceptibility in Brazil, Colombia andVenezuela (Araque et al., 2000; Gales et al., 1997; Jones et al.,1997). While at that time this phenomenon was solely attributedto the production of TEM- and SHV-like ESBL in Venezuela,Brazil witnessed the first description of CTX-M-2 and CTX-M-9 variants whereas in Argentina CTX-M-2 was already the mostprevalent ESBL among different Enterobacteriaceae such as K. pneu-moniae, E. coli, Enterobacter aerogenes, Enterobacter cloacae, Serratiamarcescens, Shigella sonnei, Salmonella enterica, Morganella mor-ganii, P. mirabilis and Providencia spp. (Bantar et al., 2000; Minariniet 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 internationaltendency, CTX-M enzymes became widespread, not only amonginpatients and outpatients over the continent, but also among spec-imens 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; Tollentinoet al., 2011). CTX-M variants described included mostly CTX-M-2though other groups such as CTX-M-1, CTX-M-9 and CTX-M-8 werealso 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 foroxyiminocephalosporins among communitary Enterobacteriaceaeis well represented in a study performed with isolates obtainedbetween 2000 and 2005 from outpatients obtained in a city locatedin Southeast Brazil. Among 257 isolates resistant to nalidixic acid,24 (9.3%) showed a positive ESBL phenotype. Among these, the CTX-M-2-like, CTX-M-9, CTX-M-8 and SHV-5 enzymes were identifiedin 13, 3, 2 and 6 isolates, respectively. This wide variety of ESBLenzymes 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) (Minariniet al., 2009).

In 2004, the occurrence of CTX-M-15, enzyme reported tohydrolyze ceftazidime more efficiently than other CTX-M variants,was reported for the first time in South America from an E. coli clin-ical isolate recovered in Peru (Pallecchi et al., 2004). Subsequently,CTX-M-15-producing E. coli were identified in clinical isolates fromBolivia and Brazil (Cergole-Novella et al., 2010; Pallecchi et al.,2007). In parallel, the incidence of CTX-M-15 among inpatients andoutpatients in Argentina during 2010 reached about 40%, suggest-ing a shift from the predominance of CTX-M-2 producers (Sennatiet al., 2012).

Other ESBL families sparsely identified in Enterobacteriaceaefrom South America, more specifically in Brazil, comprised thosebelonging to the BES and GES family, including the GES-5 variantshowing carbapenemase activity (Bonnet et al., 2000; Dropa et al.,2010; Picao et al., 2010).

Although plasmid-mediated AmpC was first described in SouthAmerica during the 1990s (FOX-1 in a K. pneumoniae clinical isolatefrom Argentina), the following report, a CMY-2 enzyme, occurred


more than 10 years later, in K. pneumoniae and Citrobacter koserii co-producing CTX-M-2 (Gonzalez et al., 1994; Rapoport et al., 2008).Of notice, posterior studies evidenced that CMY became dissemi-nated in South America during the 2000s, especially throughout the

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Table 1Chronology of resistance mechanisms affecting �-lactams, fluoroquinolones and aminoglycosides in Enterobacteriacea from South America, according to the year of isolation.

Mechanism Year of isolation Microorganism Country Reference

�-LactamaseSHV ESBL 1987 K. pneumoniae Chile Gutmann et al., 1989FOX 1989 K. pneumoniae Argentina Leiza et al. (1994)CTX-M-2-group 1990 S. Typhimurium Argentina Bauernfeind et al. (1992)PER 1990 S. Typhimurium Argentina Bauernfeind et al. (1996)BES 1996 S. marcescens Brazil Bonnet et al. (2000)CTX-M-9-group 2000 Klebsiella spp. Brazil Minarini et al. (2008a,b)CTX-M-1-group 2002 E. coli Peru Pallecchi et al. (2004)

2002 K. pneumoniae Colombia Villegas et al. (2004)CTX-M-8-group 2003 E. coli Brazil Minarini et al. (2009)IMP 2003 K. pneumoniae Brazil Lincopan et al. (2005)TEM ESBL 2004 K. pneumoniae Brazil Dropa et al. (2010)GES ESBL 2004 K. pneumoniae Brazil Dropa et al. (2010)KPC-2 2005 K. pneumoniae Colombia Villegas et al. (2006)

2005 K. pneumoniae Brazil Pavez et al. (2009)VIM 2005 K. pneumoniae Venezuela Marcano et al. (2008)CMY 2006 S. flexneri Argentina Rapoport et al. (2008)GES carbapenemase 2008 K. pneumoniae Brazil Picao et al. (2010)KPC-3 2008 K. pneumoniae Colombia Lopez et al. (2011)OXA-48 2008 K. pneumoniae Argentina Arduino et al. (2012)NDM 2011 K. pneumoniae Colombia Escobar-Perez et al. (2013)

Resistance to fluoroquinolonesQnrB 2003 C. freundii Brazil Minarini et al. (2008b)QnrA 2005 E. cloacae Brazil Minarini et al. (2007)Aac(6′)Ib-cr 2005 E. coli Peru Pallecchi et al. (2007)

QnrS 2005 E. coli Peru Pallecchiet al.(2009)

K. pneumoniae PeruK. oxytoca PeruK. pneumoniae Bolivia

Resistance to aminoglycosides

RmtD 1998 E. cloacae Argentina Tijetet al.(2011)

C. freundii ArgentinaS. marcescens Argentina

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ommunity. For instance, CMY was described in Shigella flexnerisolates recovered from bloody stool of Argentinean childrenRapoport et al., 2008). In Santiago, Chile, the prevalence oflasmid-mediated AmpC-producing P. mirabilis isolated from in-nd outpatients at a University Hospital increased from 0.17% to.5% between 2006 and 2009 (Trevino et al., 2012). The blaCMY-2ene has also been detected in E. coli isolates from hospitalizednd outpatients in Argentina as well as from community-acquiredrinary tract infections in Colombia (Jure et al., 2011; Leal et al.,013; Martinez et al., 2012). The ESBL and plasmid-mediated AmpCamilies detected to date throughout South America is depicted inig. 1A.

Regardless of the �-lactamase involved, surveillance studiesemonstrated that oxyiminocephalosporin resistant Enterobac-eriaceae have become continuously more prevalent in Southmerican hospitals, which led to massive use of carbapenemsnd the consequent emergence of carbapenem-resistant isolatesFernandez-Canigia and Dowzicky, 2012; Hawser et al., 2012;illegas et al., 2011). This phenotype has been attributed to thessociation of ESBL or AmpC-production together with porin loss,lso noticed in South American countries, as well as to the acqui-ition of carbapenemases, the most successful mechanism forarbapenem resistance among Enterobacteriaceae (Correa et al.,013; Cuzon et al., 2013; Gomez et al., 2011a; Melano et al.,003; Pavez et al., 2008; Pereira et al., 2013). Indeed, a statisti-ally significant trend for imipenem resistance among Braziliannd Argentinean K. pneumoniae isolates was recently demonstratedGales et al., 2012).


.1.2. CarbapenemasesAcquired carbapenemases inactivate virtually all �-lactams

ncluding carbapenems, antimicrobials that have been frequently

Brazil Fritsche et al. (2008)niae Brazil Bueno et al. (2013)

applied to treat nosocomial infections. These enzymes show widestructural diversity and are classified under Ambler’s classes A, Band D (Nordmann et al., 2011).

KPC (K. pneumoniae carbapenemase) is the main Ambler’sclass A carbapenemase found in South America. It was firstreported in K. pneumoniae recovered in the USA during 2001and was detected in South America 4 years later, in Colombia(Villegas et al., 2006; Yigit et al., 2001). Subsequent reports demon-strated that KPC-2-producing K. pneumoniae was also present inBrazil and Argentina since 2005 and 2006, respectively. (Pavezet al., 2009; Gomez et al., 2011b). These isolates successfullydisseminated, 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-producingisolate was reported in Chile, from a patient who came fromItaly with a history of multiple hospitalizations (Cifuentes et al.,2012).

Colombia witnessed the first South American outbreak of infec-tions due to KPC-3 producing K. pneumoniae. The index patient hadcome from Israel for a liver transplantation and the major cloneassociated with this outbreak was indistinguishable from isolatespreviously described in that country (Lopez et al., 2011). Subse-quent reports evidenced that the incidence of infections due to KPCproducers in Colombia increased from <1% in 2006 to 6% in 2009,which was associated with both clonal and polyclonal dissemi-nation KPC-3- and KPC-2-producing K. pneumoniae, respectively(Mojica et al., 2012). Of notice, KPC-3 producing K. pneumoniaefrom Colombia belonged to ST258 and the single-locus variant


ST512, comprising the Clonal Complex 11 (CC11) (Mojica et al.,2012). Even though representatives of KPC producing CC11 havesuccessfully disseminated worldwide, including throughout SouthAmerica, many KPC-2 producers reported in Brazil and Colombia

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Fig. 1. Distribution of beta-lactamases described in Enterobacteriaceae from So

re not related to this epidemic lineage (Cuzon et al., 2010; Mojicat al., 2012; Pereira et al., 2013).

KPC-2 became widespread not only in K. pneumoniae but alsomong other Enterobacteriaceae species such as E. cloacae, C. fre-ndii, E. coli, E. cloacae and S. marcescens (Cuzon et al., 2013;arcano et al., 2011; Villegas et al., 2007; Zavascki et al., 2009).

nalyses of the genetic environment of blaKPC genes provided clueso understand the success of this interspecies dissemination. Theseenes were carried by Tn4401-like structures, genetic platformsapable of high-frequency transposition (Cuzon et al., 2010). ThelaKPC-2 genes in Tn4401-like transposons have been observed inoth K. pneumoniae and non-Klebsiella spp. Enterobacteriaceae fromrazil and Colombia (Cuzon et al., 2013; Pereira et al., 2013; Picaot al., 2013).

In South America, Amber’s class B carbapenemases, also knowns metallo-beta-lactamases (MBL), were first reported upon theetection of IMP-1-producing K. pneumoniae isolates recovered inrazil during 2003 (Lincopan et al., 2005). Nevertheless, descrip-ions of enterobacteria producing IMP and VIM variants remainedcanty in the continent (Gomez et al., 2011a; Lincopan et al., 2006;arcano et al., 2008; Montealegre et al., 2011; Penteado et al.,

009). The emergence of NDM in South America, however, is likelyo differ from that registered for previous MBL, since three countriesave already described this enzyme in a short period of time.etween December 2011 and January 2012 a nosocomial outbreak


f NDM-1-producing K. pneumoniae occurred in a neonatal unit inolombia. Cases included in this outbreak did not show any epi-emiological connection with people coming from countries whereDM producers have been endemic (Escobar-Perez et al., 2013). In

merica. (A) ESBL and plasmid-mediated AmpC enzymes. (B) Carbapenemases.

June 2012, Uruguay reported NDM-producing Providencia rettgeriin hospitalized patients and in January 2013, colonized and infectedpatients with NDM-producing K. pneumoniae and P. rettgeri wereidentified in Rio Grande do Sul, Southern Brazil (ANVISA, 2013a;Carvalho-Assef et al., 2013; PAHO and WHO, 2012). Six monthslater, a pediatric patient colonized with NDM-producing E. coli andE. cloacae was reported in Rio de Janeiro (SVS, 2013). NDM detec-tion is of compulsory notification in Brazil and has mobilized greatefforts to limit the dissemination of this enzyme-encoding gene(ANVISA, 2013b; SVS, 2013).

Class D enzymes with carbapenemase activity found in Entero-bacteriaceae comprise those of the OXA-48 group. Bacteriaproducing these enzymes are found in medical institutions world-wide, and are endemic in some of them (Potron et al., 2013).However, enzymes belonging to the OXA-48 group occur stillsparsely in South America. To date, OXA-48-like enzymes were onlyobserved in K. pneumoniae and E. cloacae clinical isolates recoveredin Argentina and in K. pneumoniae from Brazil (Arduino et al., 2012;Poirel et al., 2011; Gomez et al., 2013; Jorge Luiz Mello Sampaio,personal communication). The carbapenemases detected so far inEnterobacteriaceae obtained throughout South America is depictedin Fig. 1B.

2.2. Resistance to fluoroquinolones


The most efficient mechanism of fluoroquinolone resistance isthe development of target alterations at the “quinolone-resistancedetermining region” (QRDR) of DNA Gyrase and Topoisomerase IV(Shigemura et al., 2012). However, since this is not a transferable

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echanism of resistance, the impact is limited to specific clones athe local level. Transferable resistance genes such as qnr, aac(6′)Ib-r and qep confer slight increases in fluoroquinolone minimalnhibitory concentrations. These resistance determinants may con-ribute to the development of full resistance by providing bacteriaith conditions to resist sub-inhibitory drug concentrations whileifferent regulatory adaptations or addition of further resistanceechanisms may take place (Strahilevitz et al., 2009).Between 2000 and 2005 in Brazil, qnr genes were found in

early 3% of nalidixic acid resistant enterobacterial clinical isolatesecovered from outpatients, including qnrA-in E. cloacae, qnrB2 in. coli and K. pneumoniae, and qnrB8 in C. freundii (Minarini et al.,007, 2008b). Five years later, however, a project on nalidixic-cid resistant nosocomial Enterobacteriaceae isolates from the sameeographic area showed that 12.3% carried qnr genes with the qnrB1ariant identified as the most prevalent, followed by qnrS1, qnrB2nd qnrB19 (Viana et al., 2013).

High prevalence of qnr genes has also been detected in pools ofommensal enterobacteria from healthy children from Peru andolivia, where qnrB was present in 54% and qnrS in 14% of thepecimens. Analysis of a random collection of isolates identifiedhe occurrence of qnrB19, qnrB2, qnrB10 and qnrS1; qnrB was moressociated with E. coli and qnrS with K. pneumoniae (Pallecchi et al.,009). Interestingly, qnrB19 was further identified in E. coli iso-

ates from people living in a remote Amazonian community witho evidence of undergoing selective pressure by antimicrobialsPallecchi et al., 2011). Studies concerning the genetic support ofnr demonstrated that the gene has been disseminated in Peru bymall ColE-like plasmids that lacked further antimicrobial resis-ance genes (Pallecchi et al., 2010, 2011).

The aac(6′)Ib-cr gene was an additional plasmid-mediateduinolone resistance gene detected in Peruvian healthy children.he gene was identified in a plasmid that carried blaCTX-M-15 as wellPallecchi et al., 2007). In fact, association between qnr or aac(6′)Ib-r and bla genes has been frequently reported (Cordeiro et al., 2008;inarini et al., 2008b; Quiroga et al., 2007). In addition to plasmid

romiscuity, the dissemination of these genes is favored by thelasticity of the genetic elements harboring them. A good exam-le is qnrB10 found in Argentina associated with ISCR1 elements inifferent complex class 1 integrons disseminated among C. freundii,. cloacae, E. aerogenes and K. pneumoniae isolates (Quiroga et al.,007).

Regardless of the mechanisms involved, fluoroquinolone resis-ance is undoubtedly a significant issue in South America. A recenteport including K. pneumoniae nosocomial isolates recoveredetween 2008 and 2010 indicated that resistance to fluoro-uinolones occurred in rates as high as 51.7% in Argentina, 44.4% inrazil and 47.3% in Chile (Gales et al., 2012). In the latter country,revalence of fluoroquinolone resistant E. coli in hospitals rangedrom 35% to 39% whereas 19% of isolates causing community-cquired UTI showed this phenotype (Gales et al., 2012; Silva et al.,011). In Brazil, the prevalence of ciprofloxacin-resistance among. coli isolated from community-acquired UTI during 2011 and 2012anged from 9% to 17%, depending on the region studied (Araujot al., 2011; Rocha et al., 2012).

.3. High level and broad spectrum resistance to aminoglycosides

Different mechanisms are related to aminoglycoside resistancencluding drug modifying enzymes, changes in uptake and efflux,ction of membrane proteases and target modification (Beckernd Cooper, 2013). Aminoglycoside acetyltransferase, phospho-


ransferase and nucleotidyltransferase-encoding genes have beenescribed in Enterobacteriaceae isolates in South America for morehan 20 years and are widely disseminated in the continent,ften associated with �-lactamase determinants in mobile genetic

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elements such as transposons, integrons and plasmids (Castanheiraet al., 2007; Cordeiro et al., 2008; Garcia et al., 1995; O’Brien et al.,1985; Vignoli et al., 2006).

In contrast, there are hitherto few reports on plasmid-mediated16S rRNA methyltransferases in Enterobacteriaceae from SouthAmerica. These enzymes modify the aminoglycoside binding siteat the ribosome and may confer resistance to virtually all amino-glycosides clinically available (Becker and Cooper, 2013). Themethyltransferase RmtD was characterized from a pan-resistantP. aeruginosa isolate recovered in Brazil (Doi et al., 2007). Shortlyafter, surveillance programs demonstrated that these genes werealso present in enterobacteria from South America: rmtB in E. coliand P. mirabilis in Brazil; rmtD in K. pneumoniae in Argentina, C. fre-undii in Brazil and K. pneumoniae and E. cloacae in Chile (Fritscheet al., 2008).

In 2011, rmtD2 was described in C. freundii, E. cloacae and E.aerogenes from nosocomial origin in Argentina (Tijet et al., 2011).Indeed, rmtD2 had been identified in Enterobacter spp. and C. fre-undii isolates obtained between 1996 and 1998, and these specieswere considered possible reservoirs of the genes in Argentina (Tijetet al., 2011). Isolates recovered in Argentina and Brazil had in com-mon the presence of ISCR14 in the rmtD1 and rmtD2 surroundinggenetic structure (Doi et al., 2007; Tijet et al., 2011). More recently,the new rmtG variant was described from a K. pneumoniae clini-cal isolate recovered in Brazil, showing the greatest identity withrmtD-like genes (Bueno et al., 2013). This similarity underlines thepredominance of these related gene families over other ones encod-ing 16S rRNA methyltransferases in South America.

Aminoglycosides have been considered an alternative to treatinfections caused by multidrug resistant Enterobacteriaceae, eitherassociated or not with other antimicrobials. In this case, amikacin isespecially important since resistance to gentamicin is widespreadamong clinical isolates (Hanberger et al., 2013). Indeed, gentamicinresistance rates as high as 45% for K. pneumoniae and 35% for Entero-bacter spp. have been reported in Chile and Argentina, respectively(Gales et al., 2012). Amikacin resistance rates among Enterobacteri-aceae used to be lower than 10% in the continent (Gales et al., 2011).However, considering K. pneumoniae nosocomial isolates that pro-duce ESBL, amikacin resistance rates reached 22% in Chile and 13%in Argentina (Gales et al., 2012). Moreover, amikacin resistance wasdetected in 7.5% of E. coli isolates from community acquired ITU inChile (Silva et al., 2011). Such results highlight the importance ofprudent aminoglycoside use in order to preserve its effectivenessover the next years in South America.

2.4. Resistance to polymyxin and tigecycline

Tigecycline and polymyxins are frequently the last resortantimicrobials employed to treat infections due to multidrugresistant microorganisms such as carbapenemase-producing K.pneumoniae. In general, Enterobacteriaceae resistant to these drugsare uncommon in South America. However, a rising trend forpolymyxin resistance (from 1 to 3%) was observed among K. pneu-moniae isolates obtained in Brazil, Argentina, Chile and Méxicobetween 2006 and 2009 (Gales et al., 2011). Considering isolatescollected between 2008 and 2010, colistin resistance rates were1.5% in Chile, 3.2% in Brazil and 4.7% in Argentina (Gales et al., 2012).For Enterobacter spp., these rates were even higher: 12.9%, 16.6%and 17.6% in Chile, Brazil and Argentina, respectively (Gales et al.,2012).

Published data concerning tigecycline resistance rates amongdifferent Enterobacteriaceae species collected in most South Amer-


ican countries during 2006 reveal rates ranging from 0% to 1%,except for K. pneumoniae in Colombia (2.1%) and Enterobacter spp.in Venezuela (4.5%). For Proteus and Morganella species, which aregenerally recognized as less susceptible to this antimicrobial agent,

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esistance rates reported in Venezuela, Argentina and Chile were8%, 51% and 65%, respectively (Bantar et al., 2009).

The parameter to interpret tigecycline susceptibility testingesults for Enterobacteriaceae is not definitely stated yet. CLSI doesot propose a criterion to evaluate the activity of this antimicro-ial agent. Although EUCAST categorize as resistant those isolateshowing tigecycline MIC ≥ 2 �g/ml, some studies adopt the FDAreakpoint in which isolates showing MIC ≤ 2 �g/ml are suscep-ible to this antimicrobial (EUCAST, 2013; Jones et al., 2013). Noturprisingly, surveillance of tigecycline resistance in 11 Latin Amer-can countries, including seven from South America, indicatediscrepant results depending on the criterion adopted. For instance,igecycline susceptibility rates for K. pneumoniae, Enterobacter spp.nd Serratia spp. ranged from 95.8% to 97.1% and from 90.1% to5% according to FDA’s and EUCAST’s breakpoints, respectively.. mirabilis was less susceptible, as expected, though remarkableiscrepant susceptibility rates were obtained depending on the

nterpreting criteria: 85.1% and 32.4% according to FDA and EUCAST,espectively (Jones et al., 2013).

. Political and Socioeconomic Factors likely favoringntimicrobial resistance in medical centers throughoutouth America

The organization of health systems in South American countriess not homogeneous although some overlapping features are foundmong them. For instance, public resources support major ter-iary and emergency medical centers, whereas private initiativelso finances some healthcare institutions in that region (Almeida,002). Public resources, however, decreased significantly duringhe recession of the 1980s and recovered poorly during the 1990s,hich seriously affected the quality, efficacy and equity of health

ervices in the South American continent (Almeida, 2002; Almeidat al., 2013). As a result, several medical centers experienced struc-ural deterioration, lack of qualified professionals and difficulties tocquire suitable materials and equipment therefore hampering themplementation of guidelines as well as the control of infectiousiseases and other health services (Homedes and Ugalde, 2005;opardo et al., 2011; Magluta et al., 2011; Wolff, 1993). Indeed, theurden of health-care-associated infections was shown to be higher

n developing countries compared with developed ones (Allegranzit al., 2011).

Investments in health increased significantly over the lastecade, but the allocation of resources to different areas are cur-ently not guided by a clear set of criteria or economic evaluationtudies (Iglesias et al., 2005). In addition, even if the recommenda-ions of the WHO could play a role in this decision making process,he control of both healthcare-associated infection and antimicro-ial resistance are not among the priorities included in the healthgenda for the Americas (MSHA and PAHO, 2007; PAHO and WHO,013).

Another bottleneck of health systems in South America referso the drug supply chain. The deregulation of the drug market thatook place in the 1990s led to a dramatic increase in medicines’ cost,ncluding antimicrobials. This phenomenon forced constrained-esource countries to either acquire fewer medicines or to investn less expensive drugs. This challenge was aggravated by theecognition that most South American countries do not have theppropriate structure to perform bioequivalence studies (Almeida,002; Inesta and Oteo, 2011). In this context, substandard andlso counterfeit antimicrobials gained access to this market, a


orldwide phenomenon that tends to be more prevalent amongoor countries (Almuzaini et al., 2013; Newton et al., 2006). In006, the International Medical Products Anti-Counterfeiting Task-orce, organization launched by the World Health Organization to


mitigate the production, and commercialization of fake medicines.The Taskforce estimated that nearly 10% of the global supplyof anti-infective drugs was counterfeit at that time, whereas incertain locations of Africa, Asia, and Latin America the percentageof counterfeit medicines on sale might exceed 30% (WHO andIMPACT, 2006). Unfortunately, objective data regarding the qualityof antimicrobials in South America is scarce and limited to thedescription of certain unconformities among antimalarial drugs inBrazil (Nogueira et al., 2011).

An additional challenge was posed to South American healthsystems with the institution of the patent protection for pharma-ceuticals by the Trade-Related Aspects of Intellectual PropertyRights Agreement in 1995 (WTO, 1995). The possible damage thatthis agreement could cause to developing countries’ health sys-tems motivated the implementation of a transition period, so thatadjustments in health policies and investments in internal phar-maceutical industries could be achieved before the agreementwas effectively executed. During the transition period, however,South American countries, especially Brazil and Argentina, did notprofit from mechanisms that would enable them to ensure bet-ter access to medicines including antimicrobials (Oliveira et al.,2004). The lack of data concerning the current access to antimicro-bials hampers the impact evaluation of the TRIPS agreement overanti-infective therapy in South America.

Besides the lack of resources for health systems and the frag-ile drug supply chain, compelling studies have pointed out thatlast resource broad spectrum antimicrobials are frequently mis-used in South American countries, likely due to the absence ofwell-structured antimicrobial stewardship programs (Bidone et al.,2008; Curcio, 2011; Garcia et al., 2011; Lopardo et al., 2011; Marraet al., 2009; Wirtz et al., 2013b; Wolff, 1993).

The consequence of this scenario in the context of antimicro-bial resistance is the creation of a vicious circle in which increasedcross transmission of resistant pathogens favors the dissemina-tion of difficult-to-treat infections, increases the hospital stay ofinfected patients, foments the use of large amounts of antimicro-bials that, in turn, select those organisms with greater arsenal ofresistance mechanisms that will be disseminated by healthcarestaff (Fig. 2). Indeed, studies suggest that Latin American showincreased frequency and mortality of different healthcare asso-ciated infections than developed countries as well as increasedindexes of antimicrobial-resistance (Gales et al., 2011; Jaimes,2005; Marra et al., 2011; Rosenthal et al., 2010; Wolff, 1993).

4. Factors likely favoring antimicrobial resistance in thecommunity throughout South America

4.1. Antimicrobial misuse in the community: over-the-countersales encouraging self medication

The rapid evolution and spread of antimicrobial resistance moti-vated the implementation of laws mitigating over-the-counterantimicrobial sales in many South American countries. These meas-ures need continuous surveillance in order to effectively discouragethe extensive and unnecessary dispensation at pharmacies as wellas self medication. However, studies evaluating over-the-countersales in Colombia, Venezuela and Chile revealed that only in thelatter country pharmacies were effectively selling antimicrobialsupon prescription presentation, probably as a consequence of lawreinforcement campaigns that took place in Chile. These meas-ures, however, were not as persuasive in Colombia and Venezuela


(Vacca et al., 2011; Wirtz et al., 2013a). Interestingly, although theoverall antimicrobial consumption decreased in Chile after regu-lation reinforcement, the use of ciprofloxacin and third-generationcephalosporins increased. Colombia also showed a decrease of total

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ntimicrobial consumption whereas Venezuela showed a signifi-ant increase, indicating no compliance by pharmacies (Wirtz et al.,013a). In Brazil antimicrobial sales without prescription was com-on until 2010 when the prohibition was reinforced (ANVISA,

010). Although, apparently, most Brazilian pharmacies compliedith the new regulation, especially in richer regions, no data are

vailable regarding its impact in decreasing the levels of antimicro-ial consumption in that country. Even though over-the-counterntimicrobial sales are currently being mitigated, these practicesominated for many years the market sales of street pharmaciesnd most certainly played an important role in selecting antimicro-ial resistant bacteria throughout the South America’s community.

.2. Antimicrobial resistance in the South American’ food chain

Brazil, and in lesser extend Argentina and Chile, are especiallymportant concerning the potential to disseminate antimicrobial-esistant bacteria through food in South America. These countriesre relevant producers and exporters of poultry and bovine meat,hile Chile is also the second biggest producer worldwide of

armed salmon. Production of pork meat, in contrast, is more homo-eneously distributed in different countries over the continent, andnly minimal amounts are exported (The World Bank data).

Most of the available data on resistant organisms dissemi-ated in South American food have been provided by investigatingalmonella spp. and E. coli isolates obtained from pork and chicken,oth as food producing animals and meat products. However, sinceork and pork meat are not subject to government-based surveil-

ance programs, the level of contamination with resistant bacterian these products has been estimated only from data reported inmall studies concerning resistance mainly to antimicrobial agentsther than extended spectrum �-lactams, aminoglycosides anduinolones (Ibar et al., 2009; Michael et al., 2008; San Martint al., 2008). For instance, Salmonella Brendeney isolates obtainedrom pork in Brazil presented rates of resistance over 42% foretracycline, sulphonamide, streptomycin, chloramphenicol andmpicillin. Resistant isolates carried transferable determinantset(A), tet(B), sul1, sul2, sul3, strA, catA1, floR and blaTEM encoded


n plasmids (Michael et al., 2008). Another study of Salmonellapp. involved a surveillance project of chicken meat obtained fromrazil during 2004–2006. A total of 250 Salmonella spp. isolatesere obtained from 2679 frozen chicken carcasses collected in 15

in South America and possible efforts to decelerate this course.

Brazilian cities; 53.2% were multidrug resistant. Resistance ratesover 50% were observed for streptomycin (78%), florfenicol (62%)and sulfonamide (58%). Most serotypes had relative low resistancerates to ceftriaxone (6%) and ceftiofur (28%), though SalmonellaHeidelberg showed high rates of resistance to these drugs (75%and 44%, respectively) (Medeiros et al., 2011). In fact, resistanceto oxyiminocephalosporins has not often reached high rates inSalmonella spp. from South America, though the CTX-M-2 ESBLwas described in Salmonella Typhimurium isolated from poultryin 2004 (Campioni et al., 2012; Fernandes et al., 2009; Ibar et al.,2009; Karczmarczyk et al., 2010; Michael et al., 2008; San Martinet al., 2008; Vaz et al., 2010).

Clonal distribution of Salmonella spp. among chicken, food andhumans has been documented in Brazil (Campioni et al., 2012;Vaz et al., 2010). This has been the main way of dissemination ofquinolone resistant isolates, since mutations in the QRDR is the pri-mary mechanism of resistance to this drug. A continuous growingincidence of nalidixic acid resistance in Salmonella Enteritidis fromfood and human feces associated with outbreaks of gastroenteritiswas observed in Brazil. Studies published with isolates collectedin different parts of this country showed nalidixic acid resistanceprevalence of 0.8%, 22% and 42% during the years 1985–1999,2001–2002 and 2002–2006, respectively (Campioni et al., 2012;Castro et al., 2002; Kottwitz et al., 2011; Oliveira et al., 2006).

A limited clonal composition was observed among a collectionof 128 Salmonella Enteritidis isolates obtained from human fecesand food in Brazil between 1986 and 2010, including nearly one-third of nalidixic acid-resistant isolates (Campioni et al., 2012). Notonly clonal expansion but also plasmid spread has been responsi-ble for such increase in resistance. For instance, qnrB19 has beenreported in small colE plasmids distributed in Salmonella of differ-ent serovars isolated from animals and food products in differentparts in Colombia (Karczmarczyk et al., 2010), and in Salmonellaspp. isolated from poultry and E. coli from urinary tract infectionin Brazil (Ferrari et al., 2011; Paiva et al., 2012). Considering thatquinolone resistance data presented are probably underestimated,it is reasonable to anticipate that in a few years plasmid mediateddeterminants will also play a role in quinolone resistance observed


in Salmonella clinical isolates in South America.E. coli isolates from chicken in South America present even

higher rates of resistance than Salmonella (Lapierre et al., 2008;Riccobono et al., 2012). Unfortunately, although Brazil is the biggest

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hicken exporter in the world, there is a minimum amount ofata about resistance in E. coli isolated from chicken meat pro-uced in this country (Bergenholtz et al., 2009; BPA, 2013; Dhanjit al., 2010; Warren et al., 2008). Nevertheless, CTX-M-2, CTX-M-

and CMY �-lactamase encoding genes have been all detectedn Brazilian chicken carcasses imported by European countriesDhanji et al., 2010; Warren et al., 2008). More recently, a studyeveloped in Brazil revealed that multidrug resistant E. coli iso-

ates are widely distributed in chicken meat, harboring blaCTX-M-2,laCTX-M-8, blaCTX-M-15, blaCMY-2, qnrB and qnrS genes. Of note, suchesistant strains were also recovered from organic chicken (submit-ed manuscript, Botelho, L.A.B.; Kraychete G.B.; Costa e Silva, J.L.;egis, D.V.V.; Picão, R.C.; Moreira, B.M.; Bonelli, R.R.).

No official data about antimicrobial use in livestock and chickenndustry in South America is available. Nevertheless, a possible cor-elation between high rates of resistance in E. coli obtained fromork and antimicrobials historically used as growth promoters inrgentina was hypothesized (Moredo et al., 2007). Another exam-le is provided by E. coli and Salmonella isolates from diseased pork

n Brazil. Colistin resistance rates in these isolates (6.3% and 21%,espectively) have been shown to be higher than among humanlinical isolates in the country (Gales et al., 2012; Morales et al.,012). Since colistin use is authorized in veterinary medicine, thisnding is probably a consequence of resistance evolution and selec-ive pressure (Morales et al., 2012).

In fact, although under control of restrictive legislation in Brazil,he use of antimicrobials in food producing animals is far from beinganned (MAPA, 2012). Multidrug resistant E. coli and Klebsiella spp.

solates as well as residues of �-lactams, chloramphenicol, strep-omycin, gentamicin, neomycin and tetracycline were identified inasteurized cow’s milk in Brazil (Zanella et al., 2010).

Antimicrobial abuse is also a problem in Chilean salmon indus-ry (Cabello, 2004; Millanao et al., 2011). According to officialnformation provided by the Ministerio de Economia de Chile, theeafood industry of the country has used, in 2007 and 2008, 385nd 325 tons of antimicrobials, respectively, mainly the quinolonesxolinic acid and flumequine, and also tetracycline and florfeni-ol (MEC, 2009). Also a big company that acts internationallyn salmon farming has admitted, in 2008, to make use of 560 gf antimicrobials per salmon ton produced in Chile, an amount000-fold higher than that used in Norway for the same purposeMarine Harvest, 2008; Millanao et al., 2011). Indeed, differentpecies of bacteria carrying the floR gene conferring resistance toorfenicol were isolated from salmon in Chile. Most of these iso-

ates were also multidrug resistant, showing resistance profilesith different combinations for the following antimicrobials: ampi-

illin, cefotaxime, streptomycin, gentamicin, chloramphenicol,xytetracycline, nalidixic acid, oxonilic acid and sulfamethoxa-ole:trimethoprim (Fernandez-Alarcon et al., 2010).

.3. Antimicrobial resistance in natural environments, urbanreas and aquatic matrices from South America

Although antimicrobial resistance exists in natural environ-ents as a means of warranting life for and toward antimicrobial-

roducing organisms, horizontal transfer and dissemination ofesistance genes connected to anthropogenic activities has become

matter of debate since the late 1990s (Gilliver et al., 1999;sterblad et al., 2001).

Accordingly, acquired antimicrobial resistance traits werecreened in commensal enterobacteria isolated from land iguanasnhabiting a small island in Galapagos archipelago, Ecuador. Using


his wildlife model, authors reported that acquired antimicrobialesistance determinants were absent where exposure to antibi-tics and anthropogenic activity were minimal. Moreover, wherenthropic impact was noticed, iguanas’ commensal E. coli carried


genes encoding aminoglycoside- and chloramphenicol-modifyingenzymes, TEM-like �-lactamases, as well as sul1 and tet(a) genes,sulphonamide and tetracycline encoding resistance determinants,respectively (Thaller et al., 2010). An additional study conductedwith similar purposes demonstrated that antimicrobial-resistantbacteria were more commonly isolated from reptile feces andseawater obtained from places with anthropic activity than inmore isolated or protected locations (Wheeler et al., 2012).

In Brazil, researchers evaluated the oral cavity microbiota ofsharks found in a touristic beach in Recife, where shark attacks arerelatively frequent (Interaminense et al., 2010). Enterobacteriaceaewere predominant, showing high resistance rates to penicillins,early cephalosporins and tetracycline (nearly 50% or above), aswell as to gentamicin, ciprofloxacin and chloramphenicol (10–20%).Resistance to ceftazidime, aztreonam and imipenem were alsoobserved, though less frequently (Interaminense et al., 2010).Finally, an increased number of bacteria resistant to oxytetracy-cline, oxonilic acid and florfenicol were found in marine sedimentsof Chilean salmon sea farms, when compared to control sites with-out aquaculture activity (Buschmann et al., 2012).

These descriptions support the complexities of antimicro-bial resistance dissemination throughout different organisms andniches, also depending on the levels of anthropic interference.Among the human activities favoring antimicrobial resistance, theoveruse of antimicrobials in the food chain and in medical prac-tices is especially worrisome (Fig. 2). These active molecules arefound in several environments at sub-lethal concentrations, whicheffectively drive the evolution of antimicrobial resistance by accel-erating the appearance of highly fit and stable mutants (Anderssonand Hughes, 2012).

The environment contamination by antimicrobials may alsoarise due to sewer disposal, particularly from hospitals, but alsofrom domestic and industrial settings (Andersson and Hughes,2012). The hospital wastewater is especially harmful since it con-tains a significant count of multidrug resistant bacteria togetherwith broad spectrum antimicrobials and is often disposed intoaquatic matrices without treatment (Nunez and Moretton, 2007;Picao et al., 2013). Therefore, fragile sanitation systems constituteanother important anthropogenic factor favoring the evolution ofantimicrobial resistance (Walsh and Toleman, 2012).

Reports describing antimicrobial-resistant Gram-negative rodsin sewage from South America are scarce and limited to Brazil.In that country, ESBL and KPC producing Enterobacteriaceae wereobtained from both treated and untreated sewer at a hospitalwastewater treatment plant from Rio de Janeiro (Chagas et al.,2011a,b). More recently, Enterobacteriaceae and Aeromonas spp.producing KPC were recovered from the sewer of a tertiary teach-ing hospital and also from a municipal wastewater treatment plantlocated in São Paulo, the biggest Brazilian city. In that report,KPC-producing bacteria were present in the wastewater treatmentplant’s effluent that was being discharged into an urban river (Picaoet al., 2013). KPC-producing K. pneumoniae was also recoveredfrom urban rivers in São Paulo, including the above mentioned one(Oliveira et al., 2013).

Although wastewater treatment systems were not developedto reduce the count of antimicrobial resistant bacteria, it is doc-umented that secondarily treated sewage does contain decreasedload of such bacteria compared to raw sewer (Razban et al., 2012).Updated and reliable information regarding sewage treatment inSouth America is scarce, but estimates of the Pan American HealthOrganization (PAHO) revealed low proportions of urban sewagetreated before discharge during 1995. Some of the rates were: for


Brazil 20%, Uruguay 15%, Argentina 10%, Colombia 5%, Chile 3%,Paraguay 1% and Suriname 1%. In Ecuador and Bolivia there were noeffective sewage treatment systems available at that time (UNEP,1997). However, much effort has been made to improve sanitation

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ver the last decade. Nevertheless, the continuous populationrowth and urbanization, and the complexities of the infrastruc-ure required for adequate sanitation, especially in metropolitanettings, is challenging. Official Brazilian data reveal that during001 only 25.6% of the produced sewage received any treatmentefore discharge in water courses, a rate that showed a slight

ncrease 10 years later (37.5% in 2011), despite the billions of Reaisnvested in sewage treatment infrastructure in Brazil every yearSNIS, 2011).

Human excreta and wastewater contain useful resources anday be reused for agricultural, aquiculture or industrial purposes

f defined standards are met (Blumenthal et al., 2000). How-ver, antimicrobial resistance traits were not included among thearameters applied to ascertain the security of wastewater reuse.cientific data regarding antimicrobial resistance among wastewa-er reused for multiple purposes in South America is lacking. Theingle available report on this matter so far describes a pilot projectonducted in Rio de Janeiro, Brazil, devoted to integrate a primaryewage treatment unit with fish farming, poultry feeding and theroduction of fertilizers for agriculture (Ribeiro et al., 2010). Anal-sis of water, tilapia fingerlings, organic fertilizer, vegetables andhe poultry bed of that system revealed the presence of Salmonellapp. and Aeromonas spp. Although �-lactam resistance rates wereot assessed, isolates resistant to tetracycline, chloramphenicol,ulfamethoxazole–trimethoprim and nalidixic acid were observed.f notice, Aeromonas spp. were more frequent in samples evalu-ted and showed increased resistance rates to most antimicrobialsested compared to Salmonella spp. isolates Considering all sources,16 Aeromonas spp. isolates ware obtained from 91.6% of the sam-les analyzed; 184 (44.2%) of them were resistant to at least onentimicrobial agent and 26 (6.2%) were resistant to at least threegents. In contrast, only 33 Salmonella spp. isolates were obtained,mong which 15.1% showed resistance to one or two antimicro-ials, but no one was resistance to three or more antimicrobialsRibeiro et al., 2010).

The implications of the environmental contamination byntimicrobial-resistant bacteria for human health are yet to be dis-losed. Since the persistence and dissemination extent of theseraits might be driven by specific anthropogenic activities andnvironmental characteristics, the accurate diagnosis of this threathould be preferably achieved at the local level. In this scenario,he paucity of data regarding the environmental dissemination ofntimicrobial resistance, the lack of information regarding the con-rol of antimicrobial use and wastewater reuse, and the lack ofdequate sanitation altogether suggest a detrimental scenario forublic health in South American countries (Fig. 2).

A summary of the factors driving the growing problem of antimi-robial resistance and possible interventions is presented in Fig. 2.

. Final considerations

Since bacterial dissemination does not recognize and respecteographical borders, the impact of the South American continentn the global advance of antimicrobial resistance is undoubt-dly relevant. The combination of factors such as inefficientealth systems, poor sanitation and uncontrolled use of antimi-robials provide conditions to develop and maintain resistanttrains in the hospital settings, at the community level end inhe environment in this continent. In addition, the increasingrequency of international travel and the intensive interconti-ental commerce facilitate the circulation of resistant strains.


onsequently, the problem of antimicrobial resistance in Southmerica, although a regional challenge, deserves internationalfforts. Investments in education, public health and sanitation;evelopment of guidelines for strategic antibiotic use; attempts


to facilitate the access to rapid diagnostic tools; implementationof effective and internationally connected resistance surveillanceprograms; and strict control and transparency in the antimicrobialsupply chain are some examples of measures that could help todecelerate de advance of the antimicrobial resistance in developingcountries.

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