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A dual outbreak of bloodstream infections with linezolid-resistant Staphylococcus epidermidis and Staphylococcus pettenkoferi in a liver Intensive Care Unit
International Journal of Antimicrobial Agents 40 (2012) 472–478
Contents lists available at SciVerse ScienceDirect
International Journal of Antimicrobial Agents journal homepage: http://www.elsevier.com/locate/ijantimicag
Letters to the Editor
A dual outbreak of bloodstream infections with linezolidresistant Staphylococcus epidermidis and Staphylococcus pettenkoferi in a liver Intensive Care Unit Sir, The increasing antibiotic resistance of coagulase-negative staphylococci (CoNS) has gradually reduced the range of antibiotic therapeutic options. Since 2000, linezolid has been a useful option for the treatment of these infections. In our situation of a tertiary university liver Intensive Care Unit (ICU), the fact that linezolid is cleared neither by the kidneys nor the liver and therefore dosage modification is not required in patients with altered kidney and/or liver function, unlike vancomycin, is appreciable. Three linezolid resistance mechanisms have been characterised: (i) mutations in the domain V region of 23S rRNA genes, particularly a G2576T substitution (according to Escherichia coli numbering); (ii) acquisition of the ribosomal methyltransferase gene cfr; and (iii) mutations in the ribosomal proteins L3 and L4 [1]. After almost 10 years of linezolid use in clinical practice, and although linezolid resistance remains rare among staphylococci, the emergence of linezolid resistance in CoNS has been described in different geographical regions [2]. We report the emergence of bloodstream infections involving linezolid-resistant CoNS (LR-CoNS) in a French ICU that were putatively associated with an increase in linezolid use. For the first time, these events involved two LR-CoNS species, including Staphylococcus pettenkoferi for which linezolid resistance has never previously been described. Between December 2007 and November 2010, 18 LR-CoNS were isolated from blood cultures of 16 patients hospitalised in the same ICU (15 beds) at Paul Brousse University Hospital (Paris, France), which is highly specialised in liver diseases. Patient demographic and clinical data are described in Table 1. All patients received linezolid 600 mg twice daily prior to the bacteraemia episode associated with clinical infection and central line use. Identification of isolates was performed by biochemical tests (bioMérieux, Marcy l’Étoile, France), and confirmation by sequencing of the 16S rRNA genes or matrix-assisted laser desorption ionisation–time-of-flight mass spectrometry (MALDI-TOF/MS). Antimicrobial susceptibility testing was performed using the disk diffusion method, and linezolid minimum inhibitory concentrations (MICs) were determined by the agar dilution method and were interpreted according to the recommendations of the French Society for Microbiology (http://www.sfm-microbiologie.org). LR-CoNS were screened for the presence of the cfr gene as well as mutations in 23S rRNA genes (V domain) and the L3 and L4 ribosomal proteins as previously described [3]. The gene encoding the L4 protein of S. pettenkoferi isolates was amplified using the primers L4SpettenkoferiF (CCATTGTCGCCTACCTCCTT)
and L4SpettenkoferiR (AAGGTAACGTACCAGGCCCT). Amino acid sequences were compared with those obtained from the linezolidsusceptible (MIC = 0.25 mg/L) S. pettenkoferi reference strain CIP 107711 (Centre de Ressources Biologiques de l’Institut Pasteur, Paris, France) [4]. Nine S. epidermidis isolates (linezolid MICs of 8–32 mg/L) and nine S. pettenkoferi isolates (linezolid MICs of 16 mg/L) were identified. LR-CoNS isolates harboured different mechanisms of linezolid resistance (Table 1). A C2534T mutation in 23S rDNA as well as L3 and L4 substitutions were observed in all the S. epidermidis isolates. However, Leu101Val mutation in L3 and Asn158Ser mutation in L4 have been described previously in linezolid-susceptible S. epidermidis, suggesting that these modifications are probably not involved in linezolid resistance. The G2576T mutation was identified in all linezolid-resistant S. pettenkoferi (GenBank accession no. JQ062983) compared with the 23S rDNA gene sequence from CIP 107771 (accession no. JQ062982). Mutations in ribosomal proteins were not detected in linezolid-resistant S. pettenkoferi isolates compared with those from CIP 107711 (L3, accession no. JQ062984; L4, accession no. JQ062985). The cfr gene was not detected in any of the LR-CoNS. Within each species, pulsed-field gel electrophoresis (PFGE) revealed the clonality of the strains (Table 1). These findings strongly suggest that two different strains of LR-CoNS were circulating in the ICU. Index cases of S. epidermidis and S. pettenkoferi strains were isolated in blood samples collected at 4-day intervals from the same patient after three courses of linezolid, but only one species was isolated in blood cultures from other patients. Emergence was preceded by a 110% increase in the use of linezolid in the ICU between 2007 and 2008. The particularly intensive use of linezolid should be emphasised, the rate being higher than 13 defined daily doses (DDDs)/100 patient-days, the threshold defined by Mulanovich et al. as being sufficient to generate an outbreak [5]. The genetic and epidemiological relationships between LRCoNS suggest that subsequent patients may have acquired LR-CoNS through cross-infection. The two strains may have a particular ability to spread and persist in skin flora or in the environment. S. pettenkoferi has been shown to be present in indoor dust samples [4]. In conclusion, we report here on a dual outbreak of LR-CoNS bacteraemia that for the first time involved two circulating species of Staphylococcus harbouring different mechanisms of resistance. This study reinforces the hypothesis that emergence of LR-CoNS is more the result of transmission of clonal strains than the selection of resistant mutants under treatment. The rise of linezolid resistance in CoNS has important implications regarding the use of this antibiotic, particularly for empirical therapy. To preserve the usefulness of linezolid as a therapeutic agent, judicious general use of antibiotics and the application of strict infection control measures are essential.
0924-8579/$ – see front matter © 2012 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.
Table 1 Clinical data of 16 patients with bloodstream infection due to linezolid resistant coagulase-negative staphylococci (LR-CoNS) isolates as well as phenotypic and molecular analysis of the mechanisms responsible of linezolid resistance in LR-CoNS isolates. No.
Age (years)
Gender
Underlying disease(s) or condition(s)
Days of treatment with linezolid
Date of sampling (mm/dd/yy)
16S rRNA identification
Antibiotic resistance pattern
linezolid MIC (mg/L)
Result of molecular analysis of genes conferring linezolid resistancea
1*
56
M
Acute hepatitis
2
62
M
3 4
57 48
M M
5 6 7
48 32 63
F F M
Hepatectomy, cholangiocarcinoma Acute hepatitis Acute variceal bleeding, HCV cirrhosis Acute hepatitis HELLP syndrome Cancer, gastrectomy
8
63
M
9
63
M
10
69
M
11 12
72 66
M F
13
46
M
14
63
M
15
48
M
16
51
M
Alcoholic cirrhosis, sepsis Cancer, oesophagectomy Alcoholic cirrhosis, acute variceal bleeding Hepatectomy HCV cirrhosis, liver transplantation HCV cirrhosis, HIV, liver and renal transplantation Hepatectomy, cholangiocarcinoma Acute hepatitis, liver transplantation Alcoholic cirrhosis, HIV, liver transplantation
rrlA
rrlB
rrlC
rrlD
rrlE
rrlF
L3 (rplC gene)
L4 (rplD gene)
55c 59 11
12/14/2007 01/12/2008 06/08/2008
S. epidermidis S. pettenkoferi S. pettenkoferi
GEN/ERY/CLI/OFX/SXT/RIF MET/ERY/CLI/OFX MET/ERY/CLI/OFX
32 16 16
WT WT WT
WT G2576T G2576T
WT G2576T G2576T
WT G2576T G2576T
WT G2576T G2576T
C2534T G2576T G2576T
L101V/F147L/A157R WT WT
N158S/K68R WT WT
A B B
12 24
06/11/2008 07/04/2008
S. pettenkoferi S. epidermidis
MET/ERY/CLI/OFX GEN/ERY/CLI/OFX/SXT/RIF
16 32
WT WT
G2576T WT
G2576T WT
G2576T WT
G2576T WT
G2576T C2534T
WT L101V/F147L/A157R
WT N158S/K68R
B A
11 14 15 6
09/21/2008 11/24/2008 12/16/2008 12/18/2008 02/02/2009
S. epidermidis S. epidermidis S. epidermidis S. epidermidis S. epidermidis
GEN/ERY/CLI/OFX/SXT/RIF MET/GEN/ERY/CLI/OFX/SXT/RIF GEN/ERY/CLI/OFX/SXT/RIF GEN/ERY/CLI/OFX/SXT/RIF MET/GEN/ERY/CLI/OFX/RIF
32 32 32 32 16
WT WT WT WT WT
WT WT WT WT WT
WT WT WT WT WT
WT WT WT WT WT
WT WT WT WT WT
C2534T C2534T C2534T C2534T C2534T
A157R L101V/F147L/A157R L101V/F147L/A157R L101V/F147L/A157R L101V/F147L/A157R
N158S/K68R N158S/K68R N158S/K68R N158S/K68R N158S/K68R
A A1 A A2 A1
15
02/04/2009
S. epidermidis
GEN/ERY/CLI/OFX/SXT/RIF
8
WT
WT
WT
WT
WT
C2534T
L101V/F147L/A157R
N158S/K68R
A
17
10/13/2009
S. epidermidis
MET/GEN/ERY/CLI/OFX/RIF/PT
32
WT
WT
WT
WT
WT
C2534T
L101V/F147L/A157R
N158S/K68R
A3
10 10
04/18/2010 05/06/2010
S. pettenkoferi S. pettenkoferi
MET/ERY/CLI/OFX MET/ERY/CLI/OFX
16 16
WT WT
G2576T G2576T
G2576T G2576T
G2576T G2576T
G2576T G2576T
G2576T G2576T
WT WT
WT WT
B B
10
09/24/2010
S. pettenkoferi
MET/ERY/CLI/OFX
16
WT
G2576T
G2576T
G2576T
G2576T
G2576T
WT
WT
B
15
09/29/2010
S. pettenkoferi
MET/ERY/CLI/OFX
16
WT
G2576T
G2576T
G2576T
G2576T
G2576T
WT
WT
B
8
10/06/2010
S. pettenkoferi
MET/ERY/CLI/OFX
16
WT
G2576T
G2576T
G2576T
G2576T
G2576T
WT
WT
B
7
11/02/2010
S. pettenkoferi
MET/ERY/CLI/OFX
16
WT
G2576T
G2576T
G2576T
G2576T
G2576T
WT
WT
B
GEN, gentamicin; ERY, erythromycin; CLI, clindamycin; OFX, ofloxacin; SXT, trimethoprim/sulfamethoxazole; RIF, rifampicin; MET, meticillin; PT, pristinamycin; WT, wild-type; HCV, hepatitis C virus; HELLP, haemolysis, elevated liver enzymes and low platelet count. a Sequences of 23S rDNA, rplC and rplD genes were compared with linezolid-susceptible Staphylococcus epidermidis ATCC 12228 (GenBank accession no. AE015929) for S. epidermidis isolates and with Staphylococcus pettenkoferi CIP 107711 strain for S. pettenkoferi isolates. b Escherichia coli numbering. c Patient 1 received three courses of 15, 25 and 15 days of linezolid. * Index case.
Letters to the Editor / International Journal of Antimicrobial Agents 40 (2012) 472–478
Domain V of 23S rDNA copiesb
PFGE pattern
473
474
Letters to the Editor / International Journal of Antimicrobial Agents 40 (2012) 472–478
Acknowledgment The authors thank Thierry Lambert for critical reading of the manuscript. Funding: GD was supported in part by a grant from the French National Academy of Medicine. Competing interests: None declared. Ethical approval: Not required.
References [1] Long KS, Vester B. Resistance to linezolid caused by modifications at its binding site on the ribosome. Antimicrob Agents Chemother 2012;56:603–12. [2] Ross JE, Farrell DJ, Mendes RE, Sader HS, Jones RN. Eight-year (2002–2009) summary of the linezolid (Zyvox® Annual Appraisal of Potency and Spectrum; ZAAPS) program in European countries. J Chemother 2011;23:71–6. [3] Mendes RE, Deshpande LM, Farrell DJ, Spanu T, Fadda G, Jones RN. Assessment of linezolid resistance mechanisms among Staphylococcus epidermidis causing bacteraemia in Rome, Italy. J Antimicrob Chemother 2010;65:2329–35. [4] Trülzsch K, Rinder H, Trcek J, Bader L, Wilhelm U, Heesemann J. “Staphylococcus pettenkoferi” a novel staphylococcal species isolated from clinical specimens. Diagn Microbiol Infect Dis 2002;43:175–82. [5] Mulanovich VE, Huband MD, McCurdy SP, Lemmon MM, Lescoe M, Jiang Y, et al. Emergence of linezolid-resistant coagulase-negative Staphylococcus in a cancer centre linked to increased linezolid utilization. J Antimicrob Chemother 2010;65:2001–4.
L. Mihaila AP-HP, Hôpital Paul Brousse, Hôpitaux universitaires Paris-Sud, Laboratoire de microbiologie, Villejuif, France G. Defrance a,b AP-HP, Hôpital Antoine Béclère, Hôpitaux universitaires Paris-Sud, Laboratoire de bactériologie et hygiène, Clamart, France b Université Paris Descartes, Sorbonne Paris Cité EA 4065, Faculté des sciences pharmaceutiques et biologiques, Paris, France a
E. Levesque P. Ichai AP-HP, Hôpital Paul Brousse, Hôpitaux universitaires Paris-Sud, Centre hépato-biliaire, Villejuif, France F. Garnier Hôpital Dupuytren, Laboratoire de microbiologie, Limoges, France V. Derouin J.W. Decousser AP-HP, Hôpital Antoine Béclère, Hôpitaux universitaires Paris-Sud, Laboratoire de bactériologie et hygiène, Clamart, France c
F. Doucet-Populaire c,d AP-HP, Hôpital Antoine Béclère, Hôpitaux universitaires Paris-Sud, Laboratoire de bactériologie et hygiène, Clamart, France d Université Paris Sud, EA 4043, USC INRA, Faculté de pharmacie, Châtenay-Malabry, France
N. Bourgeois-Nicolaos e,f,∗ AP-HP, Hôpital Antoine Béclère, Hôpitaux universitaires Paris-Sud, Laboratoire de bactériologie et hygiène, Clamart, France Université Paris Descartes, Sorbonne Paris Cité EA 4065, Faculté des sciences pharmaceutiques et biologiques, Paris, France
e
f
∗ Corresponding
author. Present address: AP-HP, Hôpital Antoine Béclère, Laboratoire de bactériologie et hygiène, 157 rue de la Porte de Trivaux, 92141 Clamart, France. Tel.: +33 1 45 37 46 31; fax: +33 1 46 32 67 96. E-mail address: [email protected] (N. Bourgeois-Nicolaos) 5 June 2012
doi:10.1016/j.ijantimicag.2012.06.014
Evaluation of vancomycin serum trough concentrations and outcomes in meticillin-resistant Staphylococcus aureus bacteraemia夽 Sir, The US Centers for Disease Control and Prevention (CDC) reported 94 360 invasive infections and 18 650 deaths in 2005 caused by meticillin-resistant Staphylococcus aureus (MRSA) bloodstream infection (BSI) in the USA [1]. Reports of increasing failures along with higher minimum inhibitory concentrations (MICs) for S. aureus isolates to vancomycin prompted a new consensus dosing recommendation for vancomycin. In August 2009, the Infectious Diseases Society of America (IDSA) and the American Society of Hospital Pharmacists (ASHP) recommended trough serum vancomycin concentrations of 15–20 mg/L for optimal therapy of MRSA bacteraemia. These higher serum trough levels, however, have not been shown to be more therapeutically effective in comparative clinical trials. Available data on adverse reactions such as nephrotoxicity have shown vancomycin serum trough levels of >15 mg/L to be a significant predictor, however some of these studies have not controlled for other nephrotoxic agents [2–4]. In this study, 200 consecutive cases of MRSA bacteraemia treated with vancomycin were identified over an 18-month period from July 2005 to March 2007 at Henry Ford Hospital (Detroit, MI). All evaluable patients with at least one positive blood culture of MRSA were included; patients with acute renal failure on admission, dialysis and those not at steady-state post third dose were excluded. Clinical failure rates (30-day mortality, 30day recurrence of MRSA infection and/or positive blood culture ≥7 days) and nephrotoxicity (increase in serum creatinine of 0.5 mg/dL or an increase of 50%, whichever was greater, on at least two consecutive measurements from initiation of vancomycin to 3 days after treatment) were observed comparing vancomycin trough levels <15 mg/L or ≥15 mg/L [5]. Initial vancomycin serum trough values were collected within the first 72 h of admission, and definitive vancomycin serum trough values were the average of serum trough levels collected after 72 h until end of treatment. Definitive vancomycin serum trough levels were available for 104 subjects; of these, low definitive vancomycin serum trough levels were observed in 55 subjects (52.9%), with a minimum serum trough level of 8.3 mg/L. High definitive vancomycin serum trough levels (≥15 mg/L) were observed in 49 subjects (47.1%). Patient characteristics in the univariate analysis stratified by high versus low definitive vancomycin serum trough levels that were significant included age, which was higher in the ≥15 mg/L definitive trough group, Acute Physiology and Chronic Health Evaluation (APACHE) score and high-risk source of BSI. Using the broth microdilution method, the mean MIC for all isolates was 0.53 mg/L [standard deviation (S.D.) 0.23 mg/L] and, comparatively, the mean MIC value based on Etest was 2.1 mg/L (S.D. 0.47 mg/L). There was no difference between vancomycin MICs in the low versus high definitive serum trough groups via the Etest method for the isolates (P = 0.301). Clinical failure rates in the low and high definitive serum trough groups were 13% vs. 18% (P = 0.426) and it was not considered to be an independent predictor of failure (Table 1). The higher definitive serum trough variable, when included in the multivariate model with composite failure as the
夽 This study was presented in part at the 51st Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), 17–20 September 2011, Chicago, IL (abstract A-2053).
Contents lists available at SciVerse ScienceDirect
International Journal of Antimicrobial Agents journal homepage: http://www.elsevier.com/locate/ijantimicag
Letters to the Editor
A dual outbreak of bloodstream infections with linezolidresistant Staphylococcus epidermidis and Staphylococcus pettenkoferi in a liver Intensive Care Unit Sir, The increasing antibiotic resistance of coagulase-negative staphylococci (CoNS) has gradually reduced the range of antibiotic therapeutic options. Since 2000, linezolid has been a useful option for the treatment of these infections. In our situation of a tertiary university liver Intensive Care Unit (ICU), the fact that linezolid is cleared neither by the kidneys nor the liver and therefore dosage modification is not required in patients with altered kidney and/or liver function, unlike vancomycin, is appreciable. Three linezolid resistance mechanisms have been characterised: (i) mutations in the domain V region of 23S rRNA genes, particularly a G2576T substitution (according to Escherichia coli numbering); (ii) acquisition of the ribosomal methyltransferase gene cfr; and (iii) mutations in the ribosomal proteins L3 and L4 [1]. After almost 10 years of linezolid use in clinical practice, and although linezolid resistance remains rare among staphylococci, the emergence of linezolid resistance in CoNS has been described in different geographical regions [2]. We report the emergence of bloodstream infections involving linezolid-resistant CoNS (LR-CoNS) in a French ICU that were putatively associated with an increase in linezolid use. For the first time, these events involved two LR-CoNS species, including Staphylococcus pettenkoferi for which linezolid resistance has never previously been described. Between December 2007 and November 2010, 18 LR-CoNS were isolated from blood cultures of 16 patients hospitalised in the same ICU (15 beds) at Paul Brousse University Hospital (Paris, France), which is highly specialised in liver diseases. Patient demographic and clinical data are described in Table 1. All patients received linezolid 600 mg twice daily prior to the bacteraemia episode associated with clinical infection and central line use. Identification of isolates was performed by biochemical tests (bioMérieux, Marcy l’Étoile, France), and confirmation by sequencing of the 16S rRNA genes or matrix-assisted laser desorption ionisation–time-of-flight mass spectrometry (MALDI-TOF/MS). Antimicrobial susceptibility testing was performed using the disk diffusion method, and linezolid minimum inhibitory concentrations (MICs) were determined by the agar dilution method and were interpreted according to the recommendations of the French Society for Microbiology (http://www.sfm-microbiologie.org). LR-CoNS were screened for the presence of the cfr gene as well as mutations in 23S rRNA genes (V domain) and the L3 and L4 ribosomal proteins as previously described [3]. The gene encoding the L4 protein of S. pettenkoferi isolates was amplified using the primers L4SpettenkoferiF (CCATTGTCGCCTACCTCCTT)
and L4SpettenkoferiR (AAGGTAACGTACCAGGCCCT). Amino acid sequences were compared with those obtained from the linezolidsusceptible (MIC = 0.25 mg/L) S. pettenkoferi reference strain CIP 107711 (Centre de Ressources Biologiques de l’Institut Pasteur, Paris, France) [4]. Nine S. epidermidis isolates (linezolid MICs of 8–32 mg/L) and nine S. pettenkoferi isolates (linezolid MICs of 16 mg/L) were identified. LR-CoNS isolates harboured different mechanisms of linezolid resistance (Table 1). A C2534T mutation in 23S rDNA as well as L3 and L4 substitutions were observed in all the S. epidermidis isolates. However, Leu101Val mutation in L3 and Asn158Ser mutation in L4 have been described previously in linezolid-susceptible S. epidermidis, suggesting that these modifications are probably not involved in linezolid resistance. The G2576T mutation was identified in all linezolid-resistant S. pettenkoferi (GenBank accession no. JQ062983) compared with the 23S rDNA gene sequence from CIP 107771 (accession no. JQ062982). Mutations in ribosomal proteins were not detected in linezolid-resistant S. pettenkoferi isolates compared with those from CIP 107711 (L3, accession no. JQ062984; L4, accession no. JQ062985). The cfr gene was not detected in any of the LR-CoNS. Within each species, pulsed-field gel electrophoresis (PFGE) revealed the clonality of the strains (Table 1). These findings strongly suggest that two different strains of LR-CoNS were circulating in the ICU. Index cases of S. epidermidis and S. pettenkoferi strains were isolated in blood samples collected at 4-day intervals from the same patient after three courses of linezolid, but only one species was isolated in blood cultures from other patients. Emergence was preceded by a 110% increase in the use of linezolid in the ICU between 2007 and 2008. The particularly intensive use of linezolid should be emphasised, the rate being higher than 13 defined daily doses (DDDs)/100 patient-days, the threshold defined by Mulanovich et al. as being sufficient to generate an outbreak [5]. The genetic and epidemiological relationships between LRCoNS suggest that subsequent patients may have acquired LR-CoNS through cross-infection. The two strains may have a particular ability to spread and persist in skin flora or in the environment. S. pettenkoferi has been shown to be present in indoor dust samples [4]. In conclusion, we report here on a dual outbreak of LR-CoNS bacteraemia that for the first time involved two circulating species of Staphylococcus harbouring different mechanisms of resistance. This study reinforces the hypothesis that emergence of LR-CoNS is more the result of transmission of clonal strains than the selection of resistant mutants under treatment. The rise of linezolid resistance in CoNS has important implications regarding the use of this antibiotic, particularly for empirical therapy. To preserve the usefulness of linezolid as a therapeutic agent, judicious general use of antibiotics and the application of strict infection control measures are essential.
0924-8579/$ – see front matter © 2012 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.
Table 1 Clinical data of 16 patients with bloodstream infection due to linezolid resistant coagulase-negative staphylococci (LR-CoNS) isolates as well as phenotypic and molecular analysis of the mechanisms responsible of linezolid resistance in LR-CoNS isolates. No.
Age (years)
Gender
Underlying disease(s) or condition(s)
Days of treatment with linezolid
Date of sampling (mm/dd/yy)
16S rRNA identification
Antibiotic resistance pattern
linezolid MIC (mg/L)
Result of molecular analysis of genes conferring linezolid resistancea
1*
56
M
Acute hepatitis
2
62
M
3 4
57 48
M M
5 6 7
48 32 63
F F M
Hepatectomy, cholangiocarcinoma Acute hepatitis Acute variceal bleeding, HCV cirrhosis Acute hepatitis HELLP syndrome Cancer, gastrectomy
8
63
M
9
63
M
10
69
M
11 12
72 66
M F
13
46
M
14
63
M
15
48
M
16
51
M
Alcoholic cirrhosis, sepsis Cancer, oesophagectomy Alcoholic cirrhosis, acute variceal bleeding Hepatectomy HCV cirrhosis, liver transplantation HCV cirrhosis, HIV, liver and renal transplantation Hepatectomy, cholangiocarcinoma Acute hepatitis, liver transplantation Alcoholic cirrhosis, HIV, liver transplantation
rrlA
rrlB
rrlC
rrlD
rrlE
rrlF
L3 (rplC gene)
L4 (rplD gene)
55c 59 11
12/14/2007 01/12/2008 06/08/2008
S. epidermidis S. pettenkoferi S. pettenkoferi
GEN/ERY/CLI/OFX/SXT/RIF MET/ERY/CLI/OFX MET/ERY/CLI/OFX
32 16 16
WT WT WT
WT G2576T G2576T
WT G2576T G2576T
WT G2576T G2576T
WT G2576T G2576T
C2534T G2576T G2576T
L101V/F147L/A157R WT WT
N158S/K68R WT WT
A B B
12 24
06/11/2008 07/04/2008
S. pettenkoferi S. epidermidis
MET/ERY/CLI/OFX GEN/ERY/CLI/OFX/SXT/RIF
16 32
WT WT
G2576T WT
G2576T WT
G2576T WT
G2576T WT
G2576T C2534T
WT L101V/F147L/A157R
WT N158S/K68R
B A
11 14 15 6
09/21/2008 11/24/2008 12/16/2008 12/18/2008 02/02/2009
S. epidermidis S. epidermidis S. epidermidis S. epidermidis S. epidermidis
GEN/ERY/CLI/OFX/SXT/RIF MET/GEN/ERY/CLI/OFX/SXT/RIF GEN/ERY/CLI/OFX/SXT/RIF GEN/ERY/CLI/OFX/SXT/RIF MET/GEN/ERY/CLI/OFX/RIF
32 32 32 32 16
WT WT WT WT WT
WT WT WT WT WT
WT WT WT WT WT
WT WT WT WT WT
WT WT WT WT WT
C2534T C2534T C2534T C2534T C2534T
A157R L101V/F147L/A157R L101V/F147L/A157R L101V/F147L/A157R L101V/F147L/A157R
N158S/K68R N158S/K68R N158S/K68R N158S/K68R N158S/K68R
A A1 A A2 A1
15
02/04/2009
S. epidermidis
GEN/ERY/CLI/OFX/SXT/RIF
8
WT
WT
WT
WT
WT
C2534T
L101V/F147L/A157R
N158S/K68R
A
17
10/13/2009
S. epidermidis
MET/GEN/ERY/CLI/OFX/RIF/PT
32
WT
WT
WT
WT
WT
C2534T
L101V/F147L/A157R
N158S/K68R
A3
10 10
04/18/2010 05/06/2010
S. pettenkoferi S. pettenkoferi
MET/ERY/CLI/OFX MET/ERY/CLI/OFX
16 16
WT WT
G2576T G2576T
G2576T G2576T
G2576T G2576T
G2576T G2576T
G2576T G2576T
WT WT
WT WT
B B
10
09/24/2010
S. pettenkoferi
MET/ERY/CLI/OFX
16
WT
G2576T
G2576T
G2576T
G2576T
G2576T
WT
WT
B
15
09/29/2010
S. pettenkoferi
MET/ERY/CLI/OFX
16
WT
G2576T
G2576T
G2576T
G2576T
G2576T
WT
WT
B
8
10/06/2010
S. pettenkoferi
MET/ERY/CLI/OFX
16
WT
G2576T
G2576T
G2576T
G2576T
G2576T
WT
WT
B
7
11/02/2010
S. pettenkoferi
MET/ERY/CLI/OFX
16
WT
G2576T
G2576T
G2576T
G2576T
G2576T
WT
WT
B
GEN, gentamicin; ERY, erythromycin; CLI, clindamycin; OFX, ofloxacin; SXT, trimethoprim/sulfamethoxazole; RIF, rifampicin; MET, meticillin; PT, pristinamycin; WT, wild-type; HCV, hepatitis C virus; HELLP, haemolysis, elevated liver enzymes and low platelet count. a Sequences of 23S rDNA, rplC and rplD genes were compared with linezolid-susceptible Staphylococcus epidermidis ATCC 12228 (GenBank accession no. AE015929) for S. epidermidis isolates and with Staphylococcus pettenkoferi CIP 107711 strain for S. pettenkoferi isolates. b Escherichia coli numbering. c Patient 1 received three courses of 15, 25 and 15 days of linezolid. * Index case.
Letters to the Editor / International Journal of Antimicrobial Agents 40 (2012) 472–478
Domain V of 23S rDNA copiesb
PFGE pattern
473
474
Letters to the Editor / International Journal of Antimicrobial Agents 40 (2012) 472–478
Acknowledgment The authors thank Thierry Lambert for critical reading of the manuscript. Funding: GD was supported in part by a grant from the French National Academy of Medicine. Competing interests: None declared. Ethical approval: Not required.
References [1] Long KS, Vester B. Resistance to linezolid caused by modifications at its binding site on the ribosome. Antimicrob Agents Chemother 2012;56:603–12. [2] Ross JE, Farrell DJ, Mendes RE, Sader HS, Jones RN. Eight-year (2002–2009) summary of the linezolid (Zyvox® Annual Appraisal of Potency and Spectrum; ZAAPS) program in European countries. J Chemother 2011;23:71–6. [3] Mendes RE, Deshpande LM, Farrell DJ, Spanu T, Fadda G, Jones RN. Assessment of linezolid resistance mechanisms among Staphylococcus epidermidis causing bacteraemia in Rome, Italy. J Antimicrob Chemother 2010;65:2329–35. [4] Trülzsch K, Rinder H, Trcek J, Bader L, Wilhelm U, Heesemann J. “Staphylococcus pettenkoferi” a novel staphylococcal species isolated from clinical specimens. Diagn Microbiol Infect Dis 2002;43:175–82. [5] Mulanovich VE, Huband MD, McCurdy SP, Lemmon MM, Lescoe M, Jiang Y, et al. Emergence of linezolid-resistant coagulase-negative Staphylococcus in a cancer centre linked to increased linezolid utilization. J Antimicrob Chemother 2010;65:2001–4.
L. Mihaila AP-HP, Hôpital Paul Brousse, Hôpitaux universitaires Paris-Sud, Laboratoire de microbiologie, Villejuif, France G. Defrance a,b AP-HP, Hôpital Antoine Béclère, Hôpitaux universitaires Paris-Sud, Laboratoire de bactériologie et hygiène, Clamart, France b Université Paris Descartes, Sorbonne Paris Cité EA 4065, Faculté des sciences pharmaceutiques et biologiques, Paris, France a
E. Levesque P. Ichai AP-HP, Hôpital Paul Brousse, Hôpitaux universitaires Paris-Sud, Centre hépato-biliaire, Villejuif, France F. Garnier Hôpital Dupuytren, Laboratoire de microbiologie, Limoges, France V. Derouin J.W. Decousser AP-HP, Hôpital Antoine Béclère, Hôpitaux universitaires Paris-Sud, Laboratoire de bactériologie et hygiène, Clamart, France c
F. Doucet-Populaire c,d AP-HP, Hôpital Antoine Béclère, Hôpitaux universitaires Paris-Sud, Laboratoire de bactériologie et hygiène, Clamart, France d Université Paris Sud, EA 4043, USC INRA, Faculté de pharmacie, Châtenay-Malabry, France
N. Bourgeois-Nicolaos e,f,∗ AP-HP, Hôpital Antoine Béclère, Hôpitaux universitaires Paris-Sud, Laboratoire de bactériologie et hygiène, Clamart, France Université Paris Descartes, Sorbonne Paris Cité EA 4065, Faculté des sciences pharmaceutiques et biologiques, Paris, France
e
f
∗ Corresponding
author. Present address: AP-HP, Hôpital Antoine Béclère, Laboratoire de bactériologie et hygiène, 157 rue de la Porte de Trivaux, 92141 Clamart, France. Tel.: +33 1 45 37 46 31; fax: +33 1 46 32 67 96. E-mail address: [email protected] (N. Bourgeois-Nicolaos) 5 June 2012
doi:10.1016/j.ijantimicag.2012.06.014
Evaluation of vancomycin serum trough concentrations and outcomes in meticillin-resistant Staphylococcus aureus bacteraemia夽 Sir, The US Centers for Disease Control and Prevention (CDC) reported 94 360 invasive infections and 18 650 deaths in 2005 caused by meticillin-resistant Staphylococcus aureus (MRSA) bloodstream infection (BSI) in the USA [1]. Reports of increasing failures along with higher minimum inhibitory concentrations (MICs) for S. aureus isolates to vancomycin prompted a new consensus dosing recommendation for vancomycin. In August 2009, the Infectious Diseases Society of America (IDSA) and the American Society of Hospital Pharmacists (ASHP) recommended trough serum vancomycin concentrations of 15–20 mg/L for optimal therapy of MRSA bacteraemia. These higher serum trough levels, however, have not been shown to be more therapeutically effective in comparative clinical trials. Available data on adverse reactions such as nephrotoxicity have shown vancomycin serum trough levels of >15 mg/L to be a significant predictor, however some of these studies have not controlled for other nephrotoxic agents [2–4]. In this study, 200 consecutive cases of MRSA bacteraemia treated with vancomycin were identified over an 18-month period from July 2005 to March 2007 at Henry Ford Hospital (Detroit, MI). All evaluable patients with at least one positive blood culture of MRSA were included; patients with acute renal failure on admission, dialysis and those not at steady-state post third dose were excluded. Clinical failure rates (30-day mortality, 30day recurrence of MRSA infection and/or positive blood culture ≥7 days) and nephrotoxicity (increase in serum creatinine of 0.5 mg/dL or an increase of 50%, whichever was greater, on at least two consecutive measurements from initiation of vancomycin to 3 days after treatment) were observed comparing vancomycin trough levels <15 mg/L or ≥15 mg/L [5]. Initial vancomycin serum trough values were collected within the first 72 h of admission, and definitive vancomycin serum trough values were the average of serum trough levels collected after 72 h until end of treatment. Definitive vancomycin serum trough levels were available for 104 subjects; of these, low definitive vancomycin serum trough levels were observed in 55 subjects (52.9%), with a minimum serum trough level of 8.3 mg/L. High definitive vancomycin serum trough levels (≥15 mg/L) were observed in 49 subjects (47.1%). Patient characteristics in the univariate analysis stratified by high versus low definitive vancomycin serum trough levels that were significant included age, which was higher in the ≥15 mg/L definitive trough group, Acute Physiology and Chronic Health Evaluation (APACHE) score and high-risk source of BSI. Using the broth microdilution method, the mean MIC for all isolates was 0.53 mg/L [standard deviation (S.D.) 0.23 mg/L] and, comparatively, the mean MIC value based on Etest was 2.1 mg/L (S.D. 0.47 mg/L). There was no difference between vancomycin MICs in the low versus high definitive serum trough groups via the Etest method for the isolates (P = 0.301). Clinical failure rates in the low and high definitive serum trough groups were 13% vs. 18% (P = 0.426) and it was not considered to be an independent predictor of failure (Table 1). The higher definitive serum trough variable, when included in the multivariate model with composite failure as the
夽 This study was presented in part at the 51st Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), 17–20 September 2011, Chicago, IL (abstract A-2053).