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. 2011 Jul;55(7):3579–3583. doi: 10.1128/AAC.01783-10

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 ▿

Leonardo Neves Andrade 1, Tânia Curiao 2, Joseane Cristina Ferreira 1, Juliana Mucedola Longo 1, Eduardo Carneiro Clímaco 1, Roberto Martinez 3, Fernando Bellissimo-Rodrigues 3, Aníbal Basile-Filho 3, Marco Antônio Evaristo 3, Pedro F Del Peloso 4, Vanessa Bley Ribeiro 5, Afonso Luis Barth 5, Milena Cristina Paula 6, Fernando Baquero 2, Rafael Cantón 2, Ana Lúcia da Costa Darini 1, Teresa M Coque 2,*
PMCID: PMC3122403  PMID: 21576442

Abstract

This article reports the spread of blaKPC-2 in the Sao Paulo and Rio de Janeiro states, facilitated by globally spread K. pneumoniae clonal complex 258 (CC258) clones (ST258, ST11, and ST437) and a diversity of plasmids (IncFII, IncN, and IncL/M, two untypeable plasmids carrying Tn4401a or Tn4401b) successfully disseminated among species of the Enterobacteriaceae (Enterobacter cloacae, Serratia marcescens, and Citrobacter freundii). It also constitutes the first description of sequence type 258 (ST258) in Brazil, which was associated with a nosocomial hospital outbreak in Ribeirao Preto city.

TEXT

KPC (Klebsiella pneumoniae carbapenemase) enzymes are globally spread β-lactamases of Ambler class A, comprising 10 variants, KPC-2 and KPC-3 being predominant (26; http://www.lahey.org/studies/). They are mainly associated with K. pneumoniae, although KPC producers of other Enterobacteriaceae species, Pseudomonas and Acinetobacter, are increasingly reported (26, 39). The blaKPC genes are part of Tn4401, which is often linked to mosaic platforms derived from Tn1331, a transposon containing blaOXA-9 and blaTEM-1 (24, 33). Expansion of clones and plasmids that have acquired Tn4401 seems to have fuelled the recent pandemic dissemination of blaKPC genes (8, 15, 20, 21, 34). To date, only sporadic cases of K. pneumoniae, Enterobacter cloacae, Serratia marcescens, and Escherichia coli KPC-2 producers have been documented in Brazil (6, 9, 11, 19, 23, 28, 35, 40).

We analyzed 64 carbapenem-resistant isolates: 57 K. pneumoniae isolates, 5 E. cloacae isolates, 1 S. marcescens isolate, and 1 Citrobacter freundii isolate from different patients at 6 hospitals in two distant Brazilian regions (Table 1 and Fig. 1). Identification and antimicrobial susceptibility testing were accomplished by using semiautomatic systems and standard methods (7, 13). Clonal relatedness was established by pulsed-field gel electrophoresis (PFGE) and also by multilocus sequence typing in the case K. pneumoniae isolates (http://www.pasteur.fr/recherche/genopole/PF8/mlst/Kpneumoniae.html). Characterization of KPC-2 producers included phenotypic assays, PCR, and further sequencing as reported previously (8).

Table 1.

Plasmids carrying blaKPC-2 genes in Enterobacteriaceae from Brazila

Inc group Size (kb)b Tn4401 variant Other beta-lactamases Species ST PFGE patternc Susceptibility phenotyped No. of isolates Datee City/state Sample
FIIs 50, 130, 240 a OXA-9, TEM-1, SHV-1 K. pneumoniae ST258 KpA GEN 34 03/2007–06/2008 Ribeirao Preto/SP Several samplesf
FIIs 50, 130, 240 a OXA-9, TEM-1, SHV-1 K. pneumoniae ST258 KpA1 GEN 1 06/2007 Ribeirao Preto/SP Surgical wound
FIIs 50, 130, 240 a OXA-9, TEM-1, SHV-1 K. pneumoniae ST258 KpA2 GEN 2 02–06/2008 Ribeirao Preto/SP Bronco-alveolar lavage; urine
FIIs 130, 150, 270 a OXA-9, TEM-1, SHV-1 K. pneumoniae ST258 KpA GEN 1 04/2007 Franca/SP Urine
FIIs 130 a OXA-9, TEM-1, SHV-1 K. pneumoniae ST258 KpA GEN 7 07–08/2009 Ribeirao Preto/SP Rectal swab
FIIs 130 a OXA-9, TEM-1, SHV-1 K. pneumoniae ST258 KpA1′ GEN 3 07–08/2009 Ribeirao Preto/SP Rectal swab
FIIs 130 a OXA-9, TEM-1, SHV-1 K. pneumoniae ST258 KpA4 GEN 2 08/2009 Ribeirao Preto/SP Rectal swab
FIIs 130 a OXA-9, TEM-1, SHV-1 K. pneumoniae ST258 KpA4′ GEN 1 08/2009 Ribeirao Preto/SP Rectal swab
FIIs 130, 240 a OXA-9, TEM-1, SHV-1 K. pneumoniae ST11g KpA6 GEN, AMI, TOB 1 07/2009 Ribeirao Preto/SP Rectal swab
FIIs 130, 140, 160 a OXA-9, TEM-1, SHV-1, CTX-M-2 K. pneumoniae ST48 KpE AMI, CIP, LEV, NIT, STX 1 08/2009 Ribeirao Preto/SP Rectal swab
ut 50, 110 b OXA-9, TEM-1, SHV-1, CTX-M-2 K. pneumoniae ST44 KpC GEN, AMI, TOB 2 2008–2009 Rio de Janeiro/RJ Urine
N 40, 100, 150 b OXA-9, TEM-1, SHV-1, CTX-M-2 K. pneumoniae ST327 KpB GEN, AMI, TOB 1 01/2008 Rio de Janeiro/RJ Urine
N 40, 140 b OXA-9, TEM-1, SHV-1, CTX-M-2 K. pneumoniae ST437 KpD GEN, AMI, TOB 1 2009 Rio de Janeiro/RJ Urine
N 40 b OXA-9, TEM-1 E. cloacae NA Eclα —j 2 11/2007–10/2008 Porto Alegre; Lageado/RS Fragment of foot amputated; urine
ut 20, 100, 250, 300 ut OXA-9, TEM-1 E. cloacaeh NA Eclβ — 3 01–04/2009 Porto Alegre/RS Venous catheter; urine; blood
L/M 60 b OXA-9, TEM-1 S. marcescensi NA Sm GEN 1 04/2010 Duque de Caxias/RJ Blood
L/M 50 b OXA-9, TEM-1 C. freundii NA Cf AMI 1 06/2010 Duque de Caxias/RJ Bile secretion
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a

Abbreviations: GEN, gentamicin; AMI, amikacin; TOB, tobramycin; CIP, ciprofloxacin; LEV, levofloxacin; NIT, nitrofurantoin; STX, trimethoprim-sulfamethoxazole; NA, not applicable; ut = untypeable.

b

Underlining indicates size of the plasmid carrying blaKPC-2.

c

PFGE types are defined by capital letters. Subtypes are designated by a number (indicating the number of bands that differed from those of the index strain) and primes when necessary (to distinguish among subtypes differing in the same number of bands, with such bands being different).

d

The following antibiotics were tested in this study: ampicillin, ampicillin-sulbactam, piperacillin, piperacillin-tazobactam, cefazolin, cefuroxime, cefuroxime-axetil, cefotetan, ceftazidime, ceftriaxone, cefepime, aztreonan, imipenen, meropenen, AMI, GEN, TOB, CIP, LEV, NIT, STX, colistin, and tigecycline.

e

Dates are given as month/year.

f

This clone was recovered from samples of blood (n = 10), peritoneal cavity (n = 1), oropharynx (n = 2), urine (n = 7), venous catheter (n = 7), rectal swab (n = 3), broncoalveolar lavage (n = 1), sputum (n = 1), and wound/abscess (n = 2).

g

ST11 and ST258 show highly related PFGE profiles, as has also been noted in other studies (37).

h

Strains initially described in reference 40.

i

Strain initially described in reference 11.

j

—, susceptible only to colistin and tigecycline according to EUCAST breakpoints (13).

Fig. 1.

Fig. 1.

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Geographic distribution of KPC-2-producing Enterobacteriaceae in Brazil. Abbreviations: ES, Espirito Santo; GO, Goias; DF, Distrito Federal; MG, Minas Gerais; PE, Pernambuco; RJ, Rio de Janeiro; RS, Rio Grande do Sul; SP, Sao Paulo; ND, not determined. States where KPC producers were isolated appear shaded in gray. K. pneumoniae isolates are represented by circles, E. cloacae isolates by squares, S. marcescens by a triangle, C. freundii by a hexagon, and E. coli isolates by a rhombus. Bold circles represent STs belonging to CC258 (ST258, ST11, and ST437). Clones analyzed in this study are indicated by arrows. ST25 and ST327 are double-locus variants of each other.

The K. pneumoniae isolates corresponded to 5 PFGE types linked to 6 sequence types (STs): KpA-ST258 (n = 51, comprising 6 subtypes: 42 KpA, 1 KpA1, 3 KpA1′, 2 KpA2, 2 KpA4, and 1 KpA4′), KpA6-ST11 (n = 1), KpB-ST327 (n = 1), KpC-ST44 (n = 2), KpD-ST437 (n = 1), and KpE-ST48 (n = 1). All isolates were resistant to β-lactams, susceptible to colistin and tigecycline, and showed a variable phenotype against aminoglycosides, quinolones, nitrofurantoin, and trimethoprim-sulfamethoxazole (Table 1). Heteroresistance to carbapenems was observed for K. pneumoniae and C. freundii isolates, as previously reported for KPC and VIM producers (29, 36).

The detection of isolates belonging to the multidrug-resistant K. pneumoniae clonal complex 258 (CC258) (ST258 and its single-locus variants ST11 and ST437) is of special concern (37). The ST258 clone is now globally spread and is mostly associated with the emergence and dissemination of KPC producers in different countries of North America, Europe, and Asia (2, 3, 14, 16, 20, 25, 26, 34). The ST11-K. pneumoniae lineage, first reported in France in 1997, is currently predominant in China, South Korea, and Hungary and has also been detected in the Netherlands, Norway, Poland, Portugal, Spain, and Brazil (2, 9, 17, 27, 30, 32, 35, 37; Luísa Peixe, personal communication). This clone has been extensively associated with different extended-spectrum beta-lactamases (ESBLs), mainly CTX-M-15 and CTX-M-14 (17, 27, 37) and more recently the KPC-2 (2, 30, 34) and VIM enzymes (18). Only sporadic cases of ST11 have been identified in Brazil; however, its recovery in different Brazilian cities might mirror a wider distribution than that reported (9, 35) (http://www.pasteur.fr/recherche/genopole/PF8/mlst/Kpneumoniae.html) (Fig. 1). Even though only one ST437 K. pneumoniae isolate, recovered in Rio de Janeiro in 2009, was included in our study, one recent study by Seki et al. (35) has shown the recovery of ST437 isolates producing KPC-2 in this city from 2007 to 2009, and a degree of epidemicity similar to that reported for other CC258 members cannot be discarded. Other clones recovered in this study are not well represented in the databases, such as ST327, previously detected in Israel linked to KPC-2 (21), or ST44 and ST48, which have not previously been associated with KPC production. Although most known KPC-2 producers of Serratia, Enterobacter, and Citrobacter have acquired highly transmissible plasmids from Klebsiella isolates, the spread of selected clones of these species might also be happening (31, 38).

The presence of genes encoding carbapenemases (GES, OXA, SPM, IMP, and VIM), ESBLs (CTX-M, TEM, and SHV), and cefamicinases (CMY) was analyzed as described previously (1, 10, 12). The genes blaOXA-9 and blaTEM-1 were detected in all K. pneumoniae isolates, while blaCTX-M-2 was identified in K. pneumoniae clones KpB, KpC, KpD, and KpE (Table 1). The frequent association of ESBLs or metallo-beta-lactamases (MBLs) with K. pneumoniae KPC producers in this and other studies seems to reflect acquisition of transmissible plasmids carrying blaKPC-2 by local endemic strains or transmissible plasmids carrying blaESBL by epidemic clones of KPC producers (8). The presence of CTX-M-2 among K. pneumoniae clones other than ST258 or ST11 suggests different origins, importation of globally spreading strains, and/or acquisition of KPC plasmids by endemic CTX-M-2-producing K. pneumoniae.

The analysis of the genetic environment of blaKPC by amplification of Tn4401, comparison of the restriction fragment length polymorphism (RFLP) patterns obtained by digestion of amplicons with PstI, HindIII, and BamHI, and sequencing of variants representative of distinct types revealed the presence of Tn4401 variants known as “a” (53 K. pneumoniae isolates) and “b” (4 K. pneumoniae isolates, 1 S. marcescens isolate, 1 C. freundii isolate, and 2 E. cloacae isolates) and also an untypeable platform (3 E. cloacae isolates). They were associated with a diversity of plasmids which were identified by typing the replication region (PCR and hybridization of S1-digested DNA) and comparison of fingerprintings corresponding to XhoI and HindIII-digested plasmid DNA as described previously (4, 8). While Tn4401a was located on a 130-kb IncFII plasmid, Tn4401b was detected in plasmids belonging to the incompatibility groups IncN (40 kb), IncL/M (50 to 60 kb), and two untypeable plasmids (20 and 50 kb). Only those of IncFII were transferred by conjugation.

The IncFII plasmids from ST258 K. pneumoniae isolates harboring a copy of Tn4401a were recovered in Ribeirao Preto city for 2 years. The IncN plasmids carrying the isoform Tn4401b were detected in KpB-ST327, KpD-ST437, and E. cloacae (Eclα) isolated from unrelated patients in Rio de Janeiro, Porto Alegre, and Lageado, cities sited 1,500 km apart in the south/southwest area of Brazil. IncN plasmid replicons were identical to that of pNL194, a 70-kb plasmid widely disseminated in Greece, which carries an MBL gene (22) (GenBank accession no. GU585907). A diversity of IncN plasmids with similar backbones but slightly different replicon sequences are increasingly associated with genes encoding carbapenemases of class A (KPC) or class B (VIM), reflecting the spread of IncN evolving from a common precursor (5, 15, 22). The IncL/M plasmids that also contained Tn4401b were recovered from S. marcescens and C. freundii. Cuzon et al. have recently described the location of the blaKPC-2 gene in 12-kb IncL/M plasmids from K. pneumoniae isolates collected in northeast Brazil (9), and the national dissemination of highly transferable IncL/M plasmids carrying blaKPC-2 cannot be discarded.

This article reports the spread of blaKPC-2 in Sao Paulo and Rio de Janeiro states facilitated by globally spread K. pneumoniae CC258 clones (ST258, ST11, and ST437) and a diversity of plasmids successfully disseminated among Enterobacteriaceae species. It also constitutes the first description of ST258 in Brazil associated with a nosocomial outbreak in a university hospital of Ribeirao Preto city. Although only sporadic cases of KPC producers have been documented in South America (Argentina, Colombia, and Brazil) (9, 11, 24, 40), this work has pointed out the high diversity of available genetic platforms carrying blaKPC-2. This might greatly amplify the dissemination of KPC genetic elements in this continent.

Acknowledgments

This study was funded by research grants from Conselho Nacional de Desenvolvimento Científico e Tecnológico in Brazil (CNPq, Projeto Universal, no. 480848/2008-4), the European Commission (LSHM-CT-2009-227258 HEALTH-F3-2008-223031), and the CIBERESP Network for Biomedical Research in Epidemiology and Public Health (Instituto Carlos III, Ministerio de Ciencia e Innovación of Spain, reference number CB06/02/0053). Initial identification and characterization of the strains were supported with laboratory equipment by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP). L.N.A. is supported by a CNPQ fellowship (Doutorado no País, no. 142736/2008-2) and CNPQ fellowship (Doutorado sanduíche, no. 201191/2009-1). T.C. is supported by a fellow research contract grant, FI09/00901, from Instituto Carlos III, Spanish Ministry of Science and Innovation.

We thank the staff of the Laboratory of Microbiology of Hospital das Clínicas of Faculty of Medicine of Ribeirão Preto, University of São Paulo (HC-FMRP-USP), for providing most of the isolates included in this study. We also thank personnel belonging to the infection control committee and to the intensive care unit (ICU) for supporting the investigation of intestinal colonization by carbapenemase-producing members of the Enterobacteriaceae among inpatients at the ICU of HC-FMRP-USP.

The clonal data are publicly available at http://www.pasteur.fr/mlst.

Footnotes

▿

Published ahead of print on 16 May 2011.

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