Antimicrobial resistance in Enterobacteriaceae in Brazil: focus on β-lactams and polymyxins

ABSTRACT

During the last 30 years there has been a dissemination of plasmid-mediated β-lactamases in Enterobacteriaceae in Brazil. Extended spectrum β-lactamases (ESBL) are widely disseminated in the hospital setting and are detected in a lower frequency in the community setting. Cefotaximases are the most frequently detected ESBL type and Klebsiella pneumoniae is the predominant species among ESBL producers. Klebsiella pneumoniae carbapenemase-producing Enterobacteriaceae became widely disseminated in Brazil during the last decade and KPC production is currently the most frequent resistance mechanism (96.2%) in carbapenem resistant K. pneumoniae. To date KPC-2 is the only variant reported in Brazil. Polymyxin B resistance in KPC-2-producing K. pneumoniae has come to an alarming rate of 27.1% in 2015 in São Paulo, the largest city in Brazil. New Delhi metallo-β-lactamase was detected in Brazil in 2013, has been reported in different Brazilian states but are not widely disseminated. Antimicrobial resistance in Enterobacteriaceae in Brazil is a very serious problem that needs urgent actions which includes both more strict adherence to infection control measures and more judicious use of antimicrobials.

Keywords:
ESBL; KPC; NDM; Extended spectrum β-lactamases; New Delhi metallo-β-lactamase; Klebsiella pneumoniae carbapenemase; Polymyxin B; Colistin; Antimicrobial resistance; Carbapenemases; Brazil; Enterobacteriaceae

The first reports on antimicrobial resistance in Gram-negative rods from Brazil, available at PubMed, were restricted to community-acquired infections. These reports were on sulfadiazine resistance in Escherichia coli, Shigella and Salmonella and dated from 1968.^1,2 In 1971 chloramphenicol resistance was reported in Salmonella Typhi detected in various Brazilian states³ and Shigella resistant to multiple antimicrobials were reported from Rio de Janeiro.⁴ At that time, β-lactam resistance was only reported for ampicillin.

The rise of extended-spectrum β-lactamases

Third generation cephalosporins became available for clinical use in Brazil in early 1980s. In our medical practice, we have observed resistance to third-generation cephalosporins among Enterobacteriaceae since 1985, but the first report of this finding in Brazilian hospitals was published only in 1994, describing a 52% cefepime resistance rate among ceftazidime-resistant Enterobacteriaceae.⁵ This was the first published clue on the presence of extended spectrum β-lactamases (ESBLs) in Brazil. In 1997, the first confirmation of ESBL production in Enterobacteriaceae from Brazil came out. The authors documented the presence of ESBLs in 72 K. pneumoniae clinical isolates, from private and public tertiary hospitals located in Rio de Janeiro and São Paulo, by clavulanic acid inhibition. Of note, they also reported a low susceptibility rates for amikacin (41.4%) and gentamicin (29.6%) but all isolates were still susceptible to imipenem.⁶ A subsequent work, also published in 1997, including 982 consecutive isolates from 18 hospitals, from four different states and seven different cities, was the first publication that could be used to estimate the ESBL rate among Enterobacteriaceae. Assuming that resistance to third generation cephalosporins was only due to ESBL production, 16% and 5% of K. pneumoniae and E. coli, respectively, would be classified as ESBL producers at that time.⁷

The first molecular studies on ESBLs from Brazil came out in 2000, evidencing the predominance of bla_CTX-M genes and describing the CTX-M-8 enzyme in strains other than K. pneumoniae from Rio de Janeiro.⁸ The same group of researchers described the BES-1 and the CTX-M-16 enzymes in strains from the same city.^9,10 Subsequent surveillance studies evidenced a growing ESBL production rates among Enterobacteriaceae collected from inpatients. In 2000, the ESBL production rate in K. pneumoniae collected from intensive care units was 59.2%, while these rates in Enterobacter spp. and E. coli were 19.5% and 14.6%, respectively.¹¹ The most recent study on the diversity of ESBL types in Enterobacteriaceae isolated from Brazil refers to 1827 isolates collected during the period between August 2003 and March 2008 in the city of Curitiba, Paraná. CTX-M-2 was the most frequently detected ESBL in all Enterobacteriaceae species, except in Enterobacter aerogenes, in which a CTX-M-59-producing clone was predominant.¹² Recent studies have reported that ESBL-producing Enterobacteriaceae are now detected in a significant rate in outpatients presenting cystitis. In a public institution located in Brasilia, the ESBL production rate in E. coli collected from July 2013 to April 2014 was 7.1%.¹³ When we reviewed all publication from Brazil about ESBLs, CTX-M-2 was the most frequently detected enzyme and was also detected in the largest number of different Enterobacteriaceae species (Table 1).

Table 1
Extended spectrum β-lactamases detected in Enterobacteriaceae in Brazil.

Enzyme	Species
BES-1	Serratia marcescens 9
CTX-M-1	K. pneumoniae 14
CTX-M-2	Enterobacter aerogenes12,15; Enterobacter cloacae12,16; Escherichia coli12,16-22; Klebsiella pneumoniae14,16,21,23-29; K. oxytoca21; Morganella morganii16,21; Proteus mirabilis8,17,21; Providencia stuartii16,21,30; Salmonella typhimurium31; S. marcescens17
CTX-M-3	E. coli 22
CTX-M-8	Citrobacter amalonaticus8; Enterobacter cloacae8; E. aerogenes8; E. coli12,16,22; K. pneumoniae14
CTX-M-9	Citrobacter freundii16; E. cloacae10,12; E. coli10,12,16,20; K. pneumoniae16
CTX-M-14	E. coli 18 , 32
CTX-M-15	E. aerogenes12; E. cloacae12,33; E. coli18,22,32,34; K. pneumoniae27,33,35
CTX-M-16	E. coli10; E. cloacae10
CTX-M-28	K. pneumoniae24; K. oxytoca21
CTX-M-59	E. aerogenes15; E. cloacae15; E. coli20,21,27; K. pneumoniae21,23,27
CTX-M-74	E. cloacae 16
CTX-M-75	P. stuartii 16
CTX-M-131	P. stuartii 36
GES-1	K. pneumoniae 37
GES-7	K. pneumoniae 38
PER-2	E. cloacae 12 , 15
SHV-2	K. pneumoniae; E. coli 22
SHV-4	K. pneumoniae 39
SHV-5	E. cloacae16; E. coli16,19,21; K. pneumoniae16
SHV-12	E. aerogenes12,15; E. cloacae12,15; K. pneumoniae21,25,35
SHV-27	K. pneumoniae 21 , 40
SHV-28	K. pneumoniae 21 , 41
SHV-31	K. pneumoniae 35
SHV-38	K. pneumoniae 35
SHV-40	K. pneumoniae 38
SHV-45	K. pneumoniae 21
SHV-55	K. pneumoniae 21
SHV-108	K. pneumoniae 41
SHV-122	K. pneumoniae 41
TEM-15	K. pneumoniae 21
TEM-115	K. pneumoniae 21
TEM-116	K. pneumoniae 38
TEM-135	E. cloacae 12

Plasmid-mediated AmpCs

FOX-5-like and CMY-2-like were the first plasmid-mediated AmpCs (pAmpC) reported in Brazilian isolates. Both enzymes were detected in E. coli.^42,43 The FOX-5-like encoding gene was detected during the DNA sequencing of a 41-kb conjugative plasmid that harbored a qnrA gene and a class 1 integron with the aadB and catB3 gene cassettes.⁴³ The CMY-2-like enzyme was detected in four carbapenem-resistant E. coli strains, which also possessed alteration in the outer membrane proteins, isolated from a single patient.⁴² Dias and colleagues studied the prevalence of pAmpC among Enterobacteriaceae isolated from a teaching hospital in Rio de Janeiro. In that study pAmpC encoding genes were not detected and the multidrug resistance phenotype observed in five E. coli strain was attributed to hyperexpression of chromosomally encoded AmpC.⁴⁴ Very few studies described the frequency of pAmpCs in Enterobacteriaceae in Brazil, although pAmpCs are of epidemiological importance, since carbapenem resistance can occur in strains with concomitant permeability alterations and pAmpC expression. A study conducted in a public tertiary hospital from São Paulo included 41 E. coli, five Klebsiella oxytoca, 65 Klebsiella pneumoniae, 18 P. mirabilis, and four Salmonella spp. detected during the period from January and July 2006 and found a 0.75% plasmid-mediated AmpC production rate and a single isolate producing a CMY-2-like enzyme was identified.⁴⁵ The most recent study on pAmpCs in Brazil evaluated the frequency of plasmid-mediated AmpCs in E. coli isolated from urine cultures from both outpatients and inpatients. The frequency of plasmid-mediated AmpC was 0.46% in outpatients and 1.8% in inpatients. The full nucleotide sequences were determined and bla_CMY-2 was the most frequently detected gene, but bla_CMY-4 was also detected.⁴⁶

The rise of carbapenemases in Brazil

Imipenem has been available for clinical use in Brazil since the end of the 80s. In 1989 a surveillance study, carried out with 1231 isolates, mainly from inpatients from five different medical centers from São Paulo, Rio de Janeiro and Salvador, reported a 1% imipenem resistance rate for E. coli, while this rate was 6% for Enterobacter sp. but resistant isolates were also found among K. pneumoniae.⁴⁷ In 1998, a cefpirome susceptibility study also reported imipenem resistance in Enterobacteriaceae. Using commercial microdilution plates, 349 Enterobacteriaceae from tertiary hospitals from four different states were evaluated.⁴⁸ Imipenem resistance rate among Enterobacter species varied from 2 to 8%, while this rate among K. pneumoniae was 7%, but unfortunately, no further studies were published on those strains. In 2005, almost 20 years after the introduction of carbapenems in clinical use in Brazil, the first report of an Enterobacteriaceae producing a carbapenemase came out. The work of Lincopan et al. described the presence of IMP-1 in a K. pneumoniae strain detected in a patient from a university hospital from São Paulo, located at the Southeast of Brazil.⁴⁹ The same IMP-1-producing K. pneumoniae strain was detected in six distinct hospitals of the city of São Paulo between the years 2003 and 2005.⁵⁰ In one of these hospitals, it was responsible for causing an outbreak in an intensive care unit.⁵¹ IMP-1 was also detected in a P. rettgeri isolate that was co-producer of CTX-M-like, and SHV-like.⁵⁰ The co-production of IMP-10 and KPC-2 was detected in S. marcescens causing an outbreak in a tertiary, teaching hospital in Dourados, MS.⁵²

GES-5, an enzyme of the GES family with spectrum toward carbapenems, was initially detected in Brazil in a K. pneumoniae isolated from a rectal surveillance swab of an elderly patient admitted to a private hospital in São Paulo, in 2008. This isolate also showed deletions on ompK35 and ompK36 genes.⁵³ GES-5 was also detected in three genetically related Kluyvera intermedia that were isolated from one sink and two distinct taps of an intensive care unit of a tertiary-care hospital in Porto Alegre, in May 2013, during an environmental surveillance for NDM-1-producing isolates.⁵⁴ Although only reported in 2014, GES-5 was also recovered from the blood of an adult patient admitted to a university hospital in Porto Alegre, in 2011. The patient had acute myeloid leukemia and had recent exposure to multiple antibiotics.⁵⁵

The first report on the detection of Klebsiella pneumoniae carbapenemase (KPC) in Brazil was published in 2009,⁵⁶ and described the detection of KPC-2 in 2006, ten years after the first detection of KPC-2 in world, in 1996, in North Carolina, in the United States of America.^57,58 The work described the detection of KPC-2 in K. pneumoniae in four patients from the city of Recife, located at the Northeast of Brazil. Earlier dissemination of KPC-2 production was later reported in São Paulo. Subsequently, KPC-2 was described in many Enterobacteriaceae species and locations all over Brazil (Table 2). To date this is the only variant reported from Brazil, although 23 variants (http://www.ncbi.nlm.nih.gov/pathogens/beta-lactamase-data-resources/) have been described worldwide.

Table 2
KPC-producing species detected in Brazil.

Species	Location (City, State)	MLST
C. freundii	AL59; Duque de Caxias, RJ60; GO59; RJ59	-
E. aerogenes	CE59; DF59; PE59
E. cloacae	CE59; DF59; GO59; MG59; Porto Alegre, RS60,61; Rio de Janeiro59,62	-
E. gergoviae	Recife, PE63	-
E. hormaechei	Rio de Janeiro64	-
E. coli	BA59; DF59; MG59; Recife, PE59,65; Rio de Janeiro, RJ59,66	ST259; ST3959; ST4359; ST30559; ST47959; ST50265; ST62959; ST63059; ST63159; ST63259
K. pneumoniae	AL67; AM67; Brasília, DF67; Campo Grande, MS68,69; CE67; ES67,70; Florianópolis, SC67,71; Franca, SP60; GO67,70; João Pessoa, PB72; Lageado, RS73; MA67; MG67,70; PE67,70; PI67; Porto Alegre, RS61,73,74; Recife, PE28,56,65,67,75; Ribeirão Preto, SP26,60; Rio de Janeiro, RJ14,60,67,76; São Paulo, SP27,77-80	ST1126,60,67,70,80; ST1367; ST1667,70; ST1767; ST1967; ST2567,70; ST5567; ST7070; ST10170; ST13867; ST25860; ST32367; ST34067,75; ST42370; ST43760,67,72,80; ST44270; ST44370; ST75667; ST75767; ST75867; ST75967; ST76067; ST83767; ST83867; ST83967; ST84067; ST84167; ST84267; ST85567
K. oxytoca	Recife, PE81; RJ59; MG59	-
K. georgiana	Porto Alegre, PA82	-
M. morganii	MG59	-
P. agglomerans	RJ59	-
P. mirabilis	Recife, PE83	-
P. stuartii	Recife, PE84; MG59	-
S. marcescens	Duque de Caxias, RJ60; Porto Alegre, RS61; Recife, PE59,85; Dourados, MS52	-

• The following abbreviations correspond to Brazilan States: AL, Alagoas; AM, Amazonas; BA, Bahia; DF, Distrito Federal; ES, Espírito Santo; GO, Goiás; MA, Maranhão; MG, Minas Gerais; MS, Mato Grosso do Sul; PB, Paraíba; PE, Pernambuco; RJ, Rio de Janeiro; RS, Rio Grande do Sul; SC, Santa Catarina; SP, São Paulo.

KPC-2-producing Enterobacteriaceae are now disseminated all over Brazil but K. pneumoniae is the most frequent species. Among this species, ST11 and ST437, which belong to the clonal complex 258, are the most frequently detected clonal groups (Table 2). A recent publication analyzed 3085 K. pneumoniae isolates cultivated from patients from 10 private hospitals from the great São Paulo urban area, during the period from January 2011 to December 2015. Most of the isolates were recovered from blood cultures. The work showed an amazing increase in the carbapenem resistance rate, from 6.8% in 2011 to 35.5% in 2015; of note, KPC-2 was detected in 96.2% of the carbapenem-resistant isolates, and there were both interhospital and intrahospital clonal dissemination.⁸⁰

New Delhi metallo-β-lactamase (NDM) was firstly detected in Brazil in 2013, in Providencia rettgeri, from a patient from Porto Alegre, a city located at the South of Brazil.⁸⁶ This detection occurred four years after the initial detection in a ST14 K. pneumoniae strain causing urinary tract infection and in an E. coli strain from feces from a Swedish patient of Indian origin.⁸⁷ Compared to what happened with KPC, which was detected in Brazil 10 years after the initial description, NDM-1-producing strains were detected much earlier, which indicates a great potential for more efficient dissemination in Brazil. This P. rettgeri strain was later shown to have heterogeneous carbapenem resistance, which could make its detection a challenging task.⁸⁸ Subsequently, expression of NDM-1 was reported in E. hormaechei from the same city where the first case had been detected.⁸⁹E. cloacae complex strains and Morganella morganii expressing NDM-1 were also reported by other research group from Porto Alegre.⁹⁰ In the same year of 2013, the first complete nucleotide sequences of bla_NDM-1-bearing plasmids from Brazil were described, in E. coli and E. hormaechei cultured from the same rectal swab from a patient from Rio de Janeiro who had never been exposed to carbapenems. The bla_NDM-1 gene was found to be located on a IncFIIk in E. hormaechei and on a IncX3 plasmid in a ST2 E. coli, but both plasmids contained a new structure designated Tn3000, that could possibly mediate the transposition of the bla_NDM-1 gene.⁹¹ Subsequently, coproduction of NDM-1 and KPC-2 was described in P. rettgeri and E. cloacae from Rio de Janeiro.^62,64

More recently, a new class A carbapenemase, designated Brazilian Klebsiella carbapenemase (BKC-1) was described in Brazil.⁹² To date it has only been found in K. pneumoniae in a low frequency, possible due to the fact that the bla_BKC-1 gene is located in a small transferable, non-conjugative plasmid.^92,93

Polymyxin resistance in carbapenem-resistant K. pneumoniae: a nightmare

The first report on polymyxin-resistance in Brazilian Enterobacteriaceae came out in 2006.⁹⁴ At that time, with a low colistin and polymyxin B clinical use, the polymyxin B resistance rate was 0.5% in E. coli, 1.8% in K. pneumoniae and 16.7% in Enterobacter spp. In a subsequent publication the same group evidenced a 3.0% resistance rate among K. pneumoniae in Latin America.⁹⁵ In 2013, Pereira et al. reported a 15% polymyxin resistance rate among KPC-producing K. pneumoniae from diverse Brazilian states.⁶⁷ Polymyxin resistance in E. cloacae and K. pneumoniae strains was also reported from Porto Alegre, south of Brazil.^61,96 To date, interruption of mgrB gene by insertion sequences or missense mutations is the most frequent mechanism of polymyxin resistance in K. pneumoniae in Brazil.^93,97 The most recent evidence of the amazing polymyxin resistance problem in Brazil came from a report from São Paulo, the largest city in Latin America. The authors described a 35.5% carbapenem resistance rate due to KPC-2 production, among K. pneumoniae causing infections in 2015, and also found an increase in polymyxin B resistance among KPC-producing K. pneumoniae, from 0% in 2011 to 27.1% in 2015.⁸⁰ This increase coincided with the increased use of polymyxins as empiric therapy to treat severe infectious when Gram negatives are possible etiologic agents in intensive care units. More concerning was finding interhospital and intrahospital clonal dissemination and the fact that most isolates included in the study were detected from blood cultures. This is a therapeutic nightmare, since intravenous fosfomycin and ceftazidime-avibactam are still not available in Brazil.

Recently, the mcr-1 (mobile colistin resistance) gene was detected in a clinical strain of E. coli ST101 from the Northeast of Brazil.⁹⁸ The authors found the gene located on a IncX4 plasmid, and consequently the selective pressure represented by the overuse of polymyxins could have contributed to the dissemination of this resistance mechanism.

In summary, antimicrobial resistance in Enterobacteriaceae in Brazil is a very serious problem that needs urgent actions which includes more strict adherence to infection control measures, more judicious use of antimicrobials in human and animal husbandries and fast approval of old and new antimicrobials like fosfomycin and ceftazidime-avibactam for clinical use in Brazil, in order to decrease the polymyxin consume. If these measures are not applied together, the release of ceftazidime-avibactam will be a partial measure that will be probably followed by dissemination of NDM-1 producers in Brazil.

REFERENCES

• ¹
  Fernandes MR, Trabulsi LR. Infectious resistance in pathogenic enteric organisms isolated in Sao Paulo, Brasil (preliminary report). Rev Inst Med Trop Sao Paulo 1968;10(1):52-53.
• ²
  Zuliani ME, Trabulsi LR. In vitro sensitivity of 166 Shigella strains isolated in Sao Paulo, Brazil, to sulphadiazine and five antibiotics. Rev Inst Med Trop Sao Paulo 1968;10(2):70-77.
• ³
  Costa GA, Hofer E. Resistance to chloramphenicol of Salmonella typhi samples isolated in various states of Brazil. Hospital (Rio J) 1971;79(2):229-242.
• ⁴
  Palmeira ML, Batalha PP, Gomes VL. On the appearance of multiple resistance to antibiotics and chemotherapeutic agents of Shigella strains isolated in Rio de Janeiro. Mem Inst Oswaldo Cruz 1971;69(1):145-152.
• ⁵
  Jones RN, Marshall SA. Antimicrobial activity of cefepime tested against Bush group I beta-lactamase-producing strains resistant to ceftazidime. A multilaboratory national and international clinical isolate study. Diagn Microbiol Infect Dis 1994;19(1):33-38.
• ⁶
  Gales AC, Bolmstrom A, Sampaio J, et al. Antimicrobial susceptibility of Klebsiella pneumoniae producing extended-spectrum beta-lactamase (ESBL) isolated in hospitals in Brazil. Braz J Infect Dis 1997;1(4):196-203.
• ⁷
  Sader HS, Mimica I, Rossi F, et al. Evaluation of the in vitro activity of cefepime compared to other broad-spectrum cephalosporins against clinical isolates from eighteen Brazilian hospitals by using the Etest. Diagn Microbiol Infect Dis 1997;28(2):87-92.
• ⁸
  Bonnet R, Sampaio JL, Labia R, et al. A novel CTX-M beta-lactamase (CTX-M-8) in cefotaxime-resistant Enterobacteriaceae isolated in Brazil. Antimicrob Agents Chemother 2000;44(7):1936-1942.
• ⁹
  Bonnet R, Sampaio JL, Chanal C, et al. A novel class A extended-spectrum beta-lactamase (BES-1) in Serratia marcescens isolated in Brazil. Antimicrob Agents Chemother 2000;44(11):3061-3068.
• ¹⁰
  Bonnet R, Dutour C, Sampaio JL, et al. Novel cefotaximase (CTX-M-16) with increased catalytic efficiency due to substitution Asp-240->Gly. Antimicrob Agents Chemother 2001;45(8):2269-2275.
• ¹¹
  Mendes C, Hsiung A, Kiffer C, et al. Evaluation of the in vitro activity of 9 antimicrobials against bacterial strains isolated from patients in intensive care units in brazil: MYSTIC Antimicrobial Surveillance Program. Braz J Infect Dis 2000;4(5):236-244.
• ¹²
  Nogueira Kda S, Conte D, Maia FV, et al. Distribution of extended-spectrum beta-lactamase types in a Brazilian tertiary hospital. Rev Soc Bras Med Trop 2015;48(2):162-169.
• ¹³
  Goncalves LF, de Oliveira Martins-Junior P, de Melo AB, et al. Multidrug resistance dissemination by extended-spectrum beta-lactamase-producing Escherichia coli causing community-acquired urinary tract infection in the Central-Western Region, Brazil. J Glob Antimicrob Resist 2016;6:1-4.
• ¹⁴
  Peirano G, Seki LM, Val Passos VL, et al. Carbapenem-hydrolysing beta-lactamase KPC-2 in Klebsiella pneumoniae isolated in Rio de Janeiro, Brazil. J Antimicrob Chemother 2009;63(2):265-268.
• ¹⁵
  Nogueira Kda S, Paganini MC, Conte A, et al. Emergence of extended-spectrum beta-lactamase producing Enterobacter spp. in patients with bacteremia in a tertiary hospital in southern Brazil. Enferm Infecc Microbiol Clin 2014;32(2):87-92.
• ¹⁶
  Minarini LA, Poirel L, Trevisani NA, et al. Predominance of CTX-M-type extended-spectrum beta-lactamase genes among enterobacterial isolates from outpatients in Brazil. Diagn Microbiol Infect Dis 2009;65(2):202-206.
• ¹⁷
  Andrade LN, Minarini LA, Pitondo-Silva A, et al. Determinants of beta-lactam resistance in meningitis-causing Enterobacteriaceae in Brazil. Can J Microbiol 2010;56(5):399-407.
• ¹⁸
  Berman H, Barberino MG, Moreira ED, et al. Distribution of strain type and antimicrobial susceptibility of Escherichia coli isolates causing meningitis in a large urban setting in Brazil. J Clin Microbiol 2014;52(5):1418-1422.
• ¹⁹
  Minarini LA, Camargo IL, Pitondo-Silva A, et al. Multilocus sequence typing of uropathogenic ESBL-producing Escherichia coli isolated in a Brazilian community. Curr Microbiol 2007;55(6):524-529.
• ²⁰
  Queiroz ML, Antunes P, Mourao J, et al. Characterization of extended-spectrum beta-lactamases, antimicrobial resistance genes, and plasmid content in Escherichia coli isolates from different sources in Rio de Janeiro, Brazil. Diagn Microbiol Infect Dis 2012;74(1):91-94.
• ²¹
  Dropa M, Balsalobre LC, Lincopan N, et al. Complex class 1 integrons harboring CTX-M-2-encoding genes in clinical Enterobacteriaceae from a hospital in Brazil. J Infect Dev Ctries 2015;9(8):890-897.
• ²²
  Peirano G, Asensi MD, Pitondo-Silva A, et al. Molecular characteristics of extended-spectrum beta-lactamase-producing Escherichia coli from Rio de Janeiro, Brazil. Clin Microbiol Infect 2011;17(7):1039-1043.
• ²³
  de Oliveira Garcia D, Doi Y, Szabo D, et al. Multiclonal outbreak of Klebsiella pneumoniae producing extended-spectrum beta-lactamase CTX-M-2 and novel variant CTX-M-59 in a neonatal intensive care unit in Brazil. Antimicrob Agents Chemother 2008;52(5):1790-1793.
• ²⁴
  Lopes AC, Veras DL, Lima AM, et al. bla(CTX-M-2) and bla(CTX-M-28) extended-spectrum beta-lactamase genes and class 1 integrons in clinical isolates of Klebsiella pneumoniae from Brazil. Mem Inst Oswaldo Cruz 2010;105(2):163-167.
• ²⁵
  Ramos PI, Picao RC, Almeida LG, et al. Comparative analysis of the complete genome of KPC-2-producing Klebsiella pneumoniae Kp13 reveals remarkable genome plasticity and a wide repertoire of virulence and resistance mechanisms. BMC Genomics 2014;15:54-69.
• ²⁶
  Andrade LN, Vitali L, Gaspar GG, et al. Expansion and evolution of a virulent, extensively drug-resistant (polymyxin B-resistant), QnrS1-, CTX-M-2-, and KPC-2-producing Klebsiella pneumoniae ST11 international high-risk clone. J Clin Microbiol 2014;52(7):2530-2535.
• ²⁷
  Bueno MF, Francisco GR, O’Hara JA, et al. Coproduction of 16S rRNA methyltransferase RmtD or RmtG with KPC-2 and CTX-M group extended-spectrum beta-lactamases in Klebsiella pneumoniae Antimicrob Agents Chemother 2013;57(5):2397-2400.
• ²⁸
  Cabral AB, Melo Rde C, Maciel MA, et al. Multidrug resistance genes, including bla(KPC) and bla(CTX)-M-2, among Klebsiella pneumoniae isolated in Recife, Brazil. Rev Soc Bras Med Trop 2012;45(5):572-578.
• ²⁹
  Do Carmo Filho JR, Silva RM, Castanheira M, et al. Prevalence and genetic characterization of blaCTX-M among Klebsiella pneumoniae isolates collected in an intensive care unit in Brazil. J Chemother 2008;20(5):600-603.
• ³⁰
  Zavascki AP, Carvalhaes CG, da Silva GL, et al. Outbreak of carbapenem-resistant Providencia stuartii in an intensive care unit. Infect Control Hosp Epidemiol 2012;33(6):627-630.
• ³¹
  Fernandes SA, Paterson DL, Ghilardi-Rodrigues AC, et al. CTX-M-2-producing Salmonella typhimurium isolated from pediatric patients and poultry in Brazil. Microb Drug Resist 2009;15(4):317-321.
• ³²
  Cergole-Novella MC, Guth BE, Castanheira M, et al. First description of bla(CTX-M-14)- and bla(CTX-M-15)-producing Escherichia coli isolates in Brazil. Microb Drug Resist 2010;16(3):177-184.
• ³³
  Seki LM, Pereira PS, de Souza Conceicao M, et al. Molecular epidemiology of CTX-M producing Enterobacteriaceae isolated from bloodstream infections in Rio de Janeiro, Brazil: emergence of CTX-M-15. Braz J Infect Dis 2013;17(6):640-646.
• ³⁴
  Peirano G, van der Bij AK, Freeman JL, et al. Characteristics of Escherichia coli sequence type 131 isolates that produce extended-spectrum beta-lactamases: global distribution of the H30-Rx sublineage. Antimicrob Agents Chemother 2014;58(7):3762-3767.
• ³⁵
  Tollentino FM, Polotto M, Nogueira ML, et al. High prevalence of bla(CTX-M) extended spectrum beta-lactamase genes in Klebsiella pneumoniae isolates from a tertiary care hospital: first report of bla(SHV-12), bla(SHV-31), bla(SHV-38), and bla(CTX-M-15) in Brazil. Microb Drug Resist 2011;17(1):7-16.
• ³⁶
  Dropa M, Ghiglione B, Matte MH, et al. Molecular and biochemical characterization of CTX-M-131, a natural Asp240Gly variant derived from CTX-M-2, produced by a Providencia rettgeri clinical strain in Sao Paulo, Brazil. Antimicrob Agents Chemother 2015;59(3):1815-1817.
• ³⁷
  Correa L, Martino MD, Siqueira I, et al. A hospital-based matched case-control study to identify clinical outcome and risk factors associated with carbapenem-resistant Klebsiella pneumoniae infection. BMC Infect Dis 2013;13:80-87.
• ³⁸
  Dropa M, Balsalobre LC, Lincopan N, et al. Emergence of Klebsiella pneumoniae carrying the novel extended-spectrum beta-lactamase gene variants bla(SHV-40), bla(TEM-116) and the class 1 integron-associated bla(GES-7) in Brazil. Clin Microbiol Infect 2010;16(6):630-632.
• ³⁹
  Mendes C, Kiffer C, Segura A, et al. Klebsiella pneumoniae with multiple antimicrobial resistance. Braz J Infect Dis 2004;8(1):109-111.
• ⁴⁰
  Corkill JE, Cuevas LE, Gurgel RQ, et al. SHV-27, a novel cefotaxime-hydrolysing beta-lactamase, identified in Klebsiella pneumoniae isolates from a Brazilian hospital. J Antimicrob Chemother 2001;47(4):463-465.
• ⁴¹
  Veras DL, Alves LC, Brayner FA, et al. Prevalence of the bla (SHV) gene in Klebsiella pneumoniae isolates obtained from hospital and community infections and from the microbiota of healthy individuals in Recife, Brazil. Curr Microbiol 2011;62(5):1610-1616.
• ⁴²
  Pavez M, Neves P, Dropa M, et al. Emergence of carbapenem-resistant Escherichia coli producing CMY-2-type AmpC beta-lactamase in Brazil. J Med Microbiol 2008;57(Pt 12):1590-1592.
• ⁴³
  Castanheira M, Pereira AS, Nicoletti AG, et al. First report of plasmid-mediated qnrA1 in a ciprofloxacin-resistant Escherichia coli strain in Latin America. Antimicrob Agents Chemother 2007;51(4):1527-1529.
• ⁴⁴
  da Silva Dias RC, Borges-Neto AA, D’Almeida Ferraiuoli GI, et al. Prevalence of AmpC and other beta-lactamases in enterobacteria at a large urban university hospital in Brazil. Diagn Microbiol Infect Dis 2008;60(1):79-87.
• ⁴⁵
  Campana EH, Barbosa PP, Fehlberg LC, et al. Frequency of plasmid-mediated AmpC in Enterobacteriaceae isolated in a Brazilian Teaching Hospital. Braz J Microbiol 2013;44(2):477-480.
• ⁴⁶
  Rocha DA, Campos JC, Passadore LF, et al. Frequency of plasmid-mediated AmpC beta-lactamases in Escherichia coli isolates from urine samples in Sao Paulo, Brazil. Microb Drug Resist 2016;22(4):321-327.
• ⁴⁷
  de Godoy CV, Mendes CM, Mimica I, et al. In vitro susceptibility to a new antimicrobial agent (imipenem) of pathogens isolated from inpatients at various centers. Rev Inst Med Trop Sao Paulo 1989;31(3):169-176.
• ⁴⁸
  Sader HS, Mendes CM, Montelli A, et al. In vitro antimicrobial activity of cefpirome compared to other broad-spectrum beta-lactam drugs against 804 clinical isolates from 9 Brazilian hospitals. Rev Assoc Med Bras (1992) 1998;44(4):283-288.
• ⁴⁹
  Lincopan N, McCulloch JA, Reinert C, et al. First isolation of metallo-beta-lactamase-producing multiresistant Klebsiella pneumoniae from a patient in Brazil. J Clin Microbiol 2005;43(1):516-519.
• ⁵⁰
  Lincopan N, Leis R, Vianello MA, et al. Enterobacteria producing extended-spectrum beta-lactamases and IMP-1 metallo-beta-lactamases isolated from Brazilian hospitals. J Med Microbiol 2006;55(Pt 11):1611-1613.
• ⁵¹
  Penteado AP, Castanheira M, Pignatari AC, et al. Dissemination of bla(IMP-1)-carrying integron In86 among Klebsiella pneumoniae isolates harboring a new trimethoprim resistance gene dfr23. Diagn Microbiol Infect Dis 2009;63(1):87-91.
• ⁵²
  Silva KE, Cayo R, Carvalhaes CG, et al. Coproduction of KPC-2 and IMP-10 in carbapenem-resistant Serratia marcescens isolates from an outbreak in a Brazilian Teaching Hospital. J Clin Microbiol 2015;53(7):2324-2328.
• ⁵³
  Picao RC, Santos AF, Nicoletti AG, et al. Detection of GES-5-producing Klebsiella pneumoniae in Brazil. J Antimicrob Chemother 2010;65(4):796-797.
• ⁵⁴
  Ribeiro VB, Zavascki AP, Rozales FP, et al. Detection of bla(GES-5) in carbapenem-resistant Kluyvera intermedia isolates recovered from the hospital environment. Antimicrob Agents Chemother 2014;58(1):622-623.
• ⁵⁵
  Ribeiro VB, Falci DR, Rozales FP, et al. Carbapenem-resistant GES-5-producing Klebsiella pneumoniae in Southern Brazil. Braz J Infect Dis 2014;18(2):231-232.
• ⁵⁶
  Monteiro J, Santos AF, Asensi MD, et al. First report of KPC-2-producing Klebsiella pneumoniae strains in Brazil. Antimicrob Agents Chemother 2009;53(1):333-334.
• ⁵⁷
  Yigit H, Queenan AM, Anderson GJ, et al. Novel carbapenem-hydrolyzing beta-lactamase, KPC-1, from a carbapenem-resistant strain of Klebsiella pneumoniae Antimicrob Agents Chemother 2001;45(4):1151-1161.
• ⁵⁸
  Queenan AM, Bush K. Carbapenemases: the versatile beta-lactamases. Clin Microbiol Rev 2007;20(3):440-458, table of contents.
• ⁵⁹
  Tavares CP, Pereira PS, Marques Ede A, et al. Molecular epidemiology of KPC-2-producing Enterobacteriaceae (non-Klebsiella pneumoniae) isolated from Brazil. Diagn Microbiol Infect Dis 2015;82(4):326-330.
• ⁶⁰
  Andrade LN, Curiao T, Ferreira JC, et al. Dissemination of blaKPC-2 by the spread of Klebsiella pneumoniae clonal complex 258 clones (ST258, ST11, ST437) and plasmids (IncFII, IncN, IncL/M) among Enterobacteriaceae species in Brazil. Antimicrob Agents Chemother 2011;55(7):3579-3583.
• ⁶¹
  Ribeiro VB, Andrade LN, Linhares AR, et al. Molecular characterization of Klebsiella pneumoniae carbapenemase-producing isolates in southern Brazil. J Med Microbiol 2013;62(Pt 11):1721-1727.
• ⁶²
  Quiles MG, Rocchetti TT, Fehlberg LC, et al. Unusual association of NDM-1 with KPC-2 and armA among Brazilian Enterobacteriaceae isolates. Braz J Med Biol Res 2015;48(2):174-177.
• ⁶³
  Almeida AC, de Castro KK, Fehlberg LC, et al. Carbapenem-resistant Enterobacter gergoviae harbouring blaKPC-2 in Brazil. Int J Antimicrob Agents 2014;44(4):369-370.
• ⁶⁴
  Pereira PS, Borghi M, Albano RM, et al. Coproduction of NDM-1 and KPC-2 in Enterobacter hormaechei from Brazil. Microb Drug Resist 2015;21(2):234-236.
• ⁶⁵
  Almeida AC, de Sa Cavalcanti FL, Vilela MA, et al. Escherichia coli ST502 and Klebsiella pneumoniae ST11 sharing an IncW plasmid harbouring the bla(KPC-2) gene in an Intensive Care Unit patient. Int J Antimicrob Agents 2012;40(4):374-376.
• ⁶⁶
  D'Alincourt Carvalho-Assef AP, Leao RS, da Silva RV, et al. Escherichia coli producing KPC-2 carbapenemase: first report in Brazil. Diagn Microbiol Infect Dis 2010;68(3):337-338.
• ⁶⁷
  Pereira PS, de Araujo CF, Seki LM, et al. Update of the molecular epidemiology of KPC-2-producing Klebsiella pneumoniae in Brazil: spread of clonal complex 11 (ST11, ST437 and ST340). J Antimicrob Chemother 2013;68(2):312-316.
• ⁶⁸
  Chang MR, Biberg CA, Lopes FA, et al. The first report of infection with Klebsiella pneumoniae carrying the bla(kpc) gene in State of Mato Grosso do Sul, Brazil. Rev Soc Bras Med Trop 2013;46(1):114-115.
• ⁶⁹
  Biberg CA, Rodrigues AC, do Carmo SF, et al. KPC-2-producing Klebsiella pneumoniae in a hospital in the Midwest region of Brazil. Braz J Microbiol 2015;46(2):501-504.
• ⁷⁰
  Seki LM, Pereira PS, de Souza Mda P, et al. Molecular epidemiology of KPC-2-producing Klebsiella pneumoniae isolates in Brazil: the predominance of sequence type 437. Diagn Microbiol Infect Dis 2011;70(2):274-277.
• ⁷¹
  Zavascki AP, Zoccoli CM, Machado AB, et al. KPC-2-producing Klebsiella pneumoniae in Brazil: a widespread threat in waiting? Int J Infect Dis 2010;14(6):pe539-pe540.
• ⁷²
  Fehlberg LC, Carvalho AM, Campana EH, et al. Emergence of Klebsiella pneumoniae-producing KPC-2 carbapenemase in Paraiba, Northeastern Brazil. Braz J Infect Dis 2012;16(6):577-580.
• ⁷³
  Zavascki AP, Machado AB, de Oliveira KR, et al. KPC-2-producing Enterobacter cloacae in two cities from Southern Brazil. Int J Antimicrob Agents 2009;34(3):286-288.
• ⁷⁴
  Rodrigues Perez LR, Dias CG. Emergence of infections due to a polymyxin B-resistant KPC-2-producing Klebsiella pneumoniae in critically ill patients: what is the role of a previous colonization? Infect Control Hosp Epidemiol 2016;37(2):240-241.
• ⁷⁵
  Martins WM, Almeida AC, Nicoletti AG, et al. Coproduction of KPC-2 and QnrB19 in Klebsiella pneumoniae ST340 isolate in Brazil. Diagn Microbiol Infect Dis 2015;83(4):375-376.
• ⁷⁶
  Leao RS, Pereira RH, Folescu TW, et al. KPC-2 carbapenemase-producing Klebsiella pneumoniae isolates from patients with cystic fibrosis. J Cyst Fibros 2011;10(2):140-142.
• ⁷⁷
  Pavez M, Mamizuka EM, Lincopan N. Early dissemination of KPC-2-producing Klebsiella pneumoniae strains in Brazil. Antimicrob Agents Chemother 2009;53(6):2702.
• ⁷⁸
  Beirao EM, Furtado JJ, Girardello R, et al. Clinical and microbiological characterization of KPC-producing Klebsiella pneumoniae infections in Brazil. Braz J Infect Dis. 2011;15(1):69-73.
• ⁷⁹
  Bergamasco MD, Barroso Barbosa M, de Oliveira Garcia D, et al. Infection with Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae in solid organ transplantation. Transpl Infect Dis 2012;14(2):198-205.
• ⁸⁰
  Bartolleti F, Seco BM, Capuzzo Dos Santos C, et al. Polymyxin B resistance in carbapenem-resistant Klebsiella pneumoniae, Sao Paulo, Brazil. Emerg Infect Dis 2016;22(10):1849-1851.
• ⁸¹
  Almeida AC, Cavalcanti FL, Martins WM, et al. First description of KPC-2-producing Klebsiella oxytoca in Brazil. Antimicrob Agents Chemother 2013;57(8):4077-4078.
• ⁸²
  Ribeiro VB, Zavascki AP, Nodari CS, et al. Detection of blaKPC-2 in a carbapenem-resistant Kluyvera georgiana J Antimicrob Chemother 2012;67(11):2776-2777.
• ⁸³
  Cabral AB, Maciel MA, Barros JF, et al. Detection of bla KPC-2 in Proteus mirabilis in Brazil. Rev Soc Bras Med Trop 2015;48(1):94-95.
• ⁸⁴
  Aires CA, Almeida AC, Vilela MA, et al. Selection of KPC-2-producing Providencia stuartii during treatment for septicemia. Diagn Microbiol Infect Dis 2016;84(1):95-96.
• ⁸⁵
  Margate E, Magalhaes V, Fehlberg LC, et al. KPC-producing Serratia marcescens in a home-care patient from Recife, Brazil. Rev Inst Med Trop Sao Paulo 2015;57(4):359-360.
• ⁸⁶
  Carvalho-Assef AP, Pereira PS, Albano RM, et al. Isolation of NDM-producing Providencia rettgeri in Brazil. J Antimicrob Chemother 2013;68(12):2956-2957.
• ⁸⁷
  Yong D, Toleman MA, Giske CG, et al. Characterization of a new metallo-beta-lactamase gene, bla(NDM-1), and a novel erythromycin esterase gene carried on a unique genetic structure in Klebsiella pneumoniae sequence type 14 from India. Antimicrob Agents Chemother 2009;53(12):5046-5054.
• ⁸⁸
  Zavascki AP, Falci DR, da Silva RC, et al. Heteroresistance to carbapenems in New Delhi metallo-beta-lactamase-1-producing isolates: a challenge for detection? Infect Control Hosp Epidemiol 2014;35(6):751-752.
• ⁸⁹
  Carvalho-Assef AP, Pereira PS, Albano RM, et al. Detection of NDM-1-CTX-M-15-, and qnrB4-producing Enterobacter hormaechei isolates in Brazil. Antimicrob Agents Chemother 2014;58(4):2475-2476.
• ⁹⁰
  Rozales FP, Ribeiro VB, Magagnin CM, et al. Emergence of NDM-1-producing Enterobacteriaceae in Porto Alegre, Brazil. Int J Infect Dis 2014;25:79-81.
• ⁹¹
  Campos JC, da Silva MJ, dos Santos PR, et al. Characterization of Tn3000, a transposon responsible for blaNDM-1 dissemination among Enterobacteriaceae in Brazil, Nepal, Morocco, and India. Antimicrob Agents Chemother 2015;59(12):7387-7395.
• ⁹²
  Nicoletti AG, Marcondes MF, Martins WM, et al. Characterization of BKC-1 class A carbapenemase from Klebsiella pneumoniae clinical isolates in Brazil. Antimicrob Agents Chemother 2015;59(9):5159-5164.
• ⁹³
  Martins WM, Cordeiro-Moura JR, Ramos AC, et al. Comparison of phenotypic tests for detecting BKC-1-producing Enterobacteriaceae isolates. Diagn Microbiol Infect Dis 2016;84(3):246-248.
• ⁹⁴
  Gales AC, Jones RN, Sader HS. Global assessment of the antimicrobial activity of polymyxin B against 54 731 clinical isolates of Gram-negative bacilli: report from the SENTRY antimicrobial surveillance programme (2001-2004). Clin Microbiol Infect 2006;12(4):315-321.
• ⁹⁵
  Gales AC, Jones RN, Sader HS. Contemporary activity of colistin and polymyxin B against a worldwide collection of Gram-negative pathogens: results from the SENTRY Antimicrobial Surveillance Program (2006-09). J Antimicrob Chemother 2011;66(9):2070-2074.
• ⁹⁶
  Perez LR. Evaluation of polymyxin susceptibility profile among KPC-producing Klebsiella pneumoniae using Etest and MicroScan WalkAway automated system. APMIS 2015;123(11):951-954.
• ⁹⁷
  Aires CA, Pereira PS, Asensi MD, et al. MgrB mutations mediating polymyxin B resistance in Klebsiella pneumoniae isolates from rectal surveillance swabs in Brazil. Antimicrob Agents Chemother 2016;60(11):6969-6972.
• ⁹⁸
  Fernandes MR, McCulloch JA, Vianello MA, et al. First report of the globally disseminated IncX4 plasmid carrying the mcr-1 gene in a colistin-resistant Escherichia coli sequence Type 101 isolate from a human infection in Brazil. Antimicrob Agents Chemother 2016;60(10):6415-6417.

Publication Dates

• Publication in this collection
  Dec 2016

History

• Received
  07 Oct 2016
• Accepted
  07 Oct 2016