Linezolid Resistance in Vancomycin-Resistant Enterococcus faecalis and Enterococcus faecium Isolates in a Brazilian Hospital
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Lara M. de Almeida, Maria Rita E. de Araújo, Marta F. Iwasaki, Andrey G. Sacramento, Darlan Rocha, Leila P. da Silva, Mónica Pavez, Artemir C. de Brito, Laís Carolina S. Ito, Ana C. Gales, Nilton Lincopan, Jorge L. M. Sampaio and Elsa M. Mamizuka Antimicrob. Agents Chemother. 2014, 58(5):2993. DOI: 10.1128/AAC.02399-14. Published Ahead of Print 10 March 2014.
LETTER TO THE EDITOR
Linezolid Resistance in Vancomycin-Resistant Enterococcus faecalis and Enterococcus faecium Isolates in a Brazilian Hospital Lara M. de Almeida,a Maria Rita E. de Araújo,b Marta F. Iwasaki,b Andrey G. Sacramento,a Darlan Rocha,a Leila P. da Silva,a Mónica Pavez,a Artemir C. de Brito,a Laís Carolina S. Ito,a Ana C. Gales,c Nilton Lincopan,a,d Jorge L. M. Sampaio,a Elsa M. Mamizukaa
L
inezolid resistance in vancomycin-resistant enterococci (VRE) strains has been rarely reported, with Enterococcus faecium being the species most commonly associated with these few cases (1, 2, 3). Here, we report infections due to linezolid- and vancomycin-resistant Enterococcus (LRVRE) strains in patients who were treated with linezolid in a tertiary-care hospital in Brazil. To our knowledge, this is the first report of LRVRE strains in Brazil. From August 2009 to December 2011, five E. faecalis strains and one E. faecium strain exhibiting high-level resistance to both vancomycin (MIC, ⬎256 mg/liter) and linezolid (MIC, 8 to 64 mg/liter) were isolated from blood and urine cultures from different inpatients in a Brazilian hospital (Table 1). All five subjects included were severely ill patients from intensive care units (ICUs). Patient 1 received linezolid for sepsis caused by VRE 10 days before an E. faecalis strain (18/755) was isolated from a blood culture. The regimen was changed to ampicillin, but the patient died 5 days later. Patient 2 data were not available. Patient 3 received linezolid for a period of 27 days. Two E. faecalis strains that were indistinguishable by pulsed-field gel electrophoresis (PFGE) were isolated from two blood cultures of this patient. The first strain (37/245), resistant to linezolid, was isolated at the 27th day of the total course of treatment with this drug, and the other (38/443), with intermediate resistance to linezolid, on day 53. Patient 4 received linezolid for 30 days. Eight days after the end of treatment, two strains from different species at different sites, one E. faecalis strain from a urine culture (40/ 1258) and a S. hominis strain from a blood culture, were obtained (4). Patient 6 received linezolid for a total of 32 days of treatment.
The E. faecium 42/448 strain was isolated 9 days after the end of treatment. The strains were multidrug resistant, except the E. faecalis ST525 clone, which presented intermediate erythromycin and chloramphenicol MIC values, and the E. faecalis ST526 and E. faecium ST412 clones, which were susceptible to tetracycline. All E. faecalis strains were susceptible to ampicillin. Regarding glycopeptide resistance, the vanA gene was identified in all isolates. The G2576T mutation, which confers resistance to linezolid, was identified in the 23S rRNA gene in all linezolid-resistant strains, and the incomplete digestion of domain V with NheI suggested the presence of fragments with both G2576T mutant and wild-type sequences in these strains. The cfr gene was not identified in any isolate. Multilocus sequence typing (MLST) analysis revealed that the linezolid resistance was found to occur in two novel sequence types (STs) of E. faecalis (ST525 and ST526) and in ST412 of E. faecium. Strains 50/515 and 51/426 corresponding to the linezolid-susceptible E. faecalis and E. faecium control strains showed ST62 and ST838, respectively. The emergency of LRVRE is a concerning issue. Our work contributes with data that enable observation of the course of
Published ahead of print 10 March 2014 Address correspondence to Lara M. de Almeida, [email protected]. Copyright © 2014, American Society for Microbiology. All Rights Reserved. doi:10.1128/AAC.02399-14
TABLE 1 Demographic data and antimicrobial susceptibility profiles of linezolid and vancomycin-resistant E. faecalis and E. faecium clinical strainsa Clinical specimen
PFGE type
MLST result
Glycopeptide resistance gene
23S rRNA mutation
Patient
Strain
ICU
Culture date
Total no. of treatment days
LZD
VAN
TEC
PEN
AMP
ERY
TET
CHL
CIP
LEV
1
E. faecalis 18/755 E. faecalis 28/279 E. faecalis 37/245 E. faecalis 38/443 E. faecalis 40/1258 E. faecalis 50/515b E. faecium 42/448 E. faecium 51/426b
Yes
August 2009
10
Blood
A
ST525
vanA
G2576T
8
⬎256
96
16
4
2
64
16
⬎32
⬎32
Yes
April 2010
NA
Urine
A
ST525
vanA
G2576T
16
⬎256
96
16
4
2
64
16
⬎32
⬎32
No
November 2010 January 2011 April 2011
27
Blood
A
ST525
vanA
G2576T
32
⬎256
96
16
4
2
64
16
⬎32
⬎32
2 3 3 4 5 6 7
Yes Yes No Yes No
December 2011 November 2011 December 2011
Resistance profile MIC (g/ml)
27
Blood
A
ST525
vanA
G2576T
8
⬎256
96
16
4
2
64
16
⬎32
⬎32
30
Urine
B
ST526
vanA
G2576T
16
⬎256
⬎256
16
2
⬎256
0.25
256
⬎32
⬎32
Urine
C
ST62
2
1
0.5
4
1
2
64
4
1
1
Urine
D
ST412
96
Urine
E
ST838
32
vanA
G2576T
64
⬎256
G2576T
2
⬍0.25 0.5
⬎32
512
⬎256
1
⬎256
⬎32
⬎32
8
1
8
0.5
4
0.25
0.5
a
ICU, intensive care unit; LZD, linezolid; VAN, vancomycin; TEC, teicoplanin; PEN, penicillin; AMP, ampicillin; ERY, erythromycin; TET, tetracycline; CHL, chloramphenicol; CIP, ciprofloxacin; LEV, levofloxacin. NA, data not available. Gray shading represents resistance values; boldface type represents intermediate values. b Strains 50/515 and 51/426 corresponding to the linezolid-susceptible E. faecalis and E. faecium control strains were recovered from clinical specimens obtained from other patients who were hospitalized at the same institution.
May 2014 Volume 58 Number 5
Antimicrobial Agents and Chemotherapy
p. 2993–2994
aac.asm.org
2993
Downloaded from http://aac.asm.org/ on June 21, 2014 by Universitaetsbibliothek Muenchen
Department of Clinical Analysis, School of Pharmacy, University of São Paulo, São Paulo, Brazila; Laboratory of Clinical Microbiology, Hospital Beneficência Portuguesa, São Paulo, Brazilb; Laboratory Alerta, Federal University of São Paulo, São Paulo, Brazilc; Department of Microbiology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazild
Letter to the Editor
resistance to linezolid in VRE strains, and it strengthens the idea that combination therapies with ampicillin plus an aminoglycoside can still be good therapeutic options for serious enterococcal infections. ACKNOWLEDGMENTS
REFERENCES 1. Gonzales RD, Schreckenberger PC, Graham MB, Kelkar S, DenBesten K, Quinn JP. 2001. Infections due to vancomycin-resistant Enterococcus fae-
2994
aac.asm.org
Antimicrobial Agents and Chemotherapy
Downloaded from http://aac.asm.org/ on June 21, 2014 by Universitaetsbibliothek Muenchen
This work was supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) and Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP). We declare that we have no conflicts of interest.
cium resistant to linezolid. Lancet 357:1179. http://dx.doi.org/10.1016 /S0140-6736(00)04376-2. 2. Bersos Z, Maniati M, Kontos F, Petinaki E, Maniatis AN. 2004. First report of a linezolid-resistant vancomycin-resistant Enterococcus faecium strain in Greece. J. Antimicrob. Chemother. 53:685– 686. http://dx.doi.org /10.1093/jac/dkh131. 3. Bae HG, Sung H, Kim MN, Lee EJ, Koo Lee S. 2006. First report of a linezolidand vancomycin-resistant Enterococcus faecium strain in Korea. Scand. J. Infect. Dis. 38:383–386. http://dx.doi.org/10.1080/00365540500372945. 4. de Almeida LM, de Araújo MR, Sacramento AG, Pavez M, de Souza AG, Rodrigues F, Gales AC, Lincopan N, Sampaio JL, Mamizuka EM. 2013. Linezolid resistance in Brazilian Staphylococcus hominis strains is associated with L3 and 23S rRNA ribosomal mutations. Antimicrob. Agents Chemother. 57:4082– 4083. doihttp://dx.doi.org/10.1128/AAC .00437-13.
Updated information and services can be found at: http://aac.asm.org/content/58/5/2993 These include: REFERENCES
CONTENT ALERTS
This article cites 4 articles, 2 of which can be accessed free at: http://aac.asm.org/content/58/5/2993#ref-list-1 Receive: RSS Feeds, eTOCs, free email alerts (when new articles cite this article), more»
Information about commercial reprint orders: http://journals.asm.org/site/misc/reprints.xhtml To subscribe to to another ASM Journal go to: http://journals.asm.org/site/subscriptions/
Downloaded from http://aac.asm.org/ on June 21, 2014 by Universitaetsbibliothek Muenchen
Lara M. de Almeida, Maria Rita E. de Araújo, Marta F. Iwasaki, Andrey G. Sacramento, Darlan Rocha, Leila P. da Silva, Mónica Pavez, Artemir C. de Brito, Laís Carolina S. Ito, Ana C. Gales, Nilton Lincopan, Jorge L. M. Sampaio and Elsa M. Mamizuka Antimicrob. Agents Chemother. 2014, 58(5):2993. DOI: 10.1128/AAC.02399-14. Published Ahead of Print 10 March 2014.
LETTER TO THE EDITOR
Linezolid Resistance in Vancomycin-Resistant Enterococcus faecalis and Enterococcus faecium Isolates in a Brazilian Hospital Lara M. de Almeida,a Maria Rita E. de Araújo,b Marta F. Iwasaki,b Andrey G. Sacramento,a Darlan Rocha,a Leila P. da Silva,a Mónica Pavez,a Artemir C. de Brito,a Laís Carolina S. Ito,a Ana C. Gales,c Nilton Lincopan,a,d Jorge L. M. Sampaio,a Elsa M. Mamizukaa
L
inezolid resistance in vancomycin-resistant enterococci (VRE) strains has been rarely reported, with Enterococcus faecium being the species most commonly associated with these few cases (1, 2, 3). Here, we report infections due to linezolid- and vancomycin-resistant Enterococcus (LRVRE) strains in patients who were treated with linezolid in a tertiary-care hospital in Brazil. To our knowledge, this is the first report of LRVRE strains in Brazil. From August 2009 to December 2011, five E. faecalis strains and one E. faecium strain exhibiting high-level resistance to both vancomycin (MIC, ⬎256 mg/liter) and linezolid (MIC, 8 to 64 mg/liter) were isolated from blood and urine cultures from different inpatients in a Brazilian hospital (Table 1). All five subjects included were severely ill patients from intensive care units (ICUs). Patient 1 received linezolid for sepsis caused by VRE 10 days before an E. faecalis strain (18/755) was isolated from a blood culture. The regimen was changed to ampicillin, but the patient died 5 days later. Patient 2 data were not available. Patient 3 received linezolid for a period of 27 days. Two E. faecalis strains that were indistinguishable by pulsed-field gel electrophoresis (PFGE) were isolated from two blood cultures of this patient. The first strain (37/245), resistant to linezolid, was isolated at the 27th day of the total course of treatment with this drug, and the other (38/443), with intermediate resistance to linezolid, on day 53. Patient 4 received linezolid for 30 days. Eight days after the end of treatment, two strains from different species at different sites, one E. faecalis strain from a urine culture (40/ 1258) and a S. hominis strain from a blood culture, were obtained (4). Patient 6 received linezolid for a total of 32 days of treatment.
The E. faecium 42/448 strain was isolated 9 days after the end of treatment. The strains were multidrug resistant, except the E. faecalis ST525 clone, which presented intermediate erythromycin and chloramphenicol MIC values, and the E. faecalis ST526 and E. faecium ST412 clones, which were susceptible to tetracycline. All E. faecalis strains were susceptible to ampicillin. Regarding glycopeptide resistance, the vanA gene was identified in all isolates. The G2576T mutation, which confers resistance to linezolid, was identified in the 23S rRNA gene in all linezolid-resistant strains, and the incomplete digestion of domain V with NheI suggested the presence of fragments with both G2576T mutant and wild-type sequences in these strains. The cfr gene was not identified in any isolate. Multilocus sequence typing (MLST) analysis revealed that the linezolid resistance was found to occur in two novel sequence types (STs) of E. faecalis (ST525 and ST526) and in ST412 of E. faecium. Strains 50/515 and 51/426 corresponding to the linezolid-susceptible E. faecalis and E. faecium control strains showed ST62 and ST838, respectively. The emergency of LRVRE is a concerning issue. Our work contributes with data that enable observation of the course of
Published ahead of print 10 March 2014 Address correspondence to Lara M. de Almeida, [email protected]. Copyright © 2014, American Society for Microbiology. All Rights Reserved. doi:10.1128/AAC.02399-14
TABLE 1 Demographic data and antimicrobial susceptibility profiles of linezolid and vancomycin-resistant E. faecalis and E. faecium clinical strainsa Clinical specimen
PFGE type
MLST result
Glycopeptide resistance gene
23S rRNA mutation
Patient
Strain
ICU
Culture date
Total no. of treatment days
LZD
VAN
TEC
PEN
AMP
ERY
TET
CHL
CIP
LEV
1
E. faecalis 18/755 E. faecalis 28/279 E. faecalis 37/245 E. faecalis 38/443 E. faecalis 40/1258 E. faecalis 50/515b E. faecium 42/448 E. faecium 51/426b
Yes
August 2009
10
Blood
A
ST525
vanA
G2576T
8
⬎256
96
16
4
2
64
16
⬎32
⬎32
Yes
April 2010
NA
Urine
A
ST525
vanA
G2576T
16
⬎256
96
16
4
2
64
16
⬎32
⬎32
No
November 2010 January 2011 April 2011
27
Blood
A
ST525
vanA
G2576T
32
⬎256
96
16
4
2
64
16
⬎32
⬎32
2 3 3 4 5 6 7
Yes Yes No Yes No
December 2011 November 2011 December 2011
Resistance profile MIC (g/ml)
27
Blood
A
ST525
vanA
G2576T
8
⬎256
96
16
4
2
64
16
⬎32
⬎32
30
Urine
B
ST526
vanA
G2576T
16
⬎256
⬎256
16
2
⬎256
0.25
256
⬎32
⬎32
Urine
C
ST62
2
1
0.5
4
1
2
64
4
1
1
Urine
D
ST412
96
Urine
E
ST838
32
vanA
G2576T
64
⬎256
G2576T
2
⬍0.25 0.5
⬎32
512
⬎256
1
⬎256
⬎32
⬎32
8
1
8
0.5
4
0.25
0.5
a
ICU, intensive care unit; LZD, linezolid; VAN, vancomycin; TEC, teicoplanin; PEN, penicillin; AMP, ampicillin; ERY, erythromycin; TET, tetracycline; CHL, chloramphenicol; CIP, ciprofloxacin; LEV, levofloxacin. NA, data not available. Gray shading represents resistance values; boldface type represents intermediate values. b Strains 50/515 and 51/426 corresponding to the linezolid-susceptible E. faecalis and E. faecium control strains were recovered from clinical specimens obtained from other patients who were hospitalized at the same institution.
May 2014 Volume 58 Number 5
Antimicrobial Agents and Chemotherapy
p. 2993–2994
aac.asm.org
2993
Downloaded from http://aac.asm.org/ on June 21, 2014 by Universitaetsbibliothek Muenchen
Department of Clinical Analysis, School of Pharmacy, University of São Paulo, São Paulo, Brazila; Laboratory of Clinical Microbiology, Hospital Beneficência Portuguesa, São Paulo, Brazilb; Laboratory Alerta, Federal University of São Paulo, São Paulo, Brazilc; Department of Microbiology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazild
Letter to the Editor
resistance to linezolid in VRE strains, and it strengthens the idea that combination therapies with ampicillin plus an aminoglycoside can still be good therapeutic options for serious enterococcal infections. ACKNOWLEDGMENTS
REFERENCES 1. Gonzales RD, Schreckenberger PC, Graham MB, Kelkar S, DenBesten K, Quinn JP. 2001. Infections due to vancomycin-resistant Enterococcus fae-
2994
aac.asm.org
Antimicrobial Agents and Chemotherapy
Downloaded from http://aac.asm.org/ on June 21, 2014 by Universitaetsbibliothek Muenchen
This work was supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) and Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP). We declare that we have no conflicts of interest.
cium resistant to linezolid. Lancet 357:1179. http://dx.doi.org/10.1016 /S0140-6736(00)04376-2. 2. Bersos Z, Maniati M, Kontos F, Petinaki E, Maniatis AN. 2004. First report of a linezolid-resistant vancomycin-resistant Enterococcus faecium strain in Greece. J. Antimicrob. Chemother. 53:685– 686. http://dx.doi.org /10.1093/jac/dkh131. 3. Bae HG, Sung H, Kim MN, Lee EJ, Koo Lee S. 2006. First report of a linezolidand vancomycin-resistant Enterococcus faecium strain in Korea. Scand. J. Infect. Dis. 38:383–386. http://dx.doi.org/10.1080/00365540500372945. 4. de Almeida LM, de Araújo MR, Sacramento AG, Pavez M, de Souza AG, Rodrigues F, Gales AC, Lincopan N, Sampaio JL, Mamizuka EM. 2013. Linezolid resistance in Brazilian Staphylococcus hominis strains is associated with L3 and 23S rRNA ribosomal mutations. Antimicrob. Agents Chemother. 57:4082– 4083. doihttp://dx.doi.org/10.1128/AAC .00437-13.
