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Papers by Arnfinn Sundsfjord

Research paper thumbnail of Investigating the mobilome in clinically important lineages of Enterococcus faecium and Enterococcus faecalis

BMC genomics, Jan 10, 2015

The success of Enterococcus faecium and E. faecalis evolving as multi-resistant nosocomial pathog... more The success of Enterococcus faecium and E. faecalis evolving as multi-resistant nosocomial pathogens is associated with their ability to acquire and share adaptive traits, including antimicrobial resistance genes encoded by mobile genetic elements (MGE). Here, we investigate this mobilome in successful hospital associated genetic lineages, E. faecium sequence type (ST)17 (n=10) and ST78 (n=10), E. faecalis ST6 (n=10) and ST40 (n=10) by DNA microarray analyses. The hybridization patterns of 272 representative targets including plasmid backbones (n=85), transposable elements (n=85), resistance determinants (n=67), prophages (n=29), and clustered regularly interspaced short palindromic repeats (CRISPR)-cas sequences (n=6) separated the strains according to species, and for E. faecalis also according to STs. RCR-, Rep_3-, RepA_N- and Inc18-family plasmids were highly prevalent and with the exception of Rep_3, evenly distributed between the species. There was a considerable difference in...

Research paper thumbnail of Multi-Locus Variable Number of Tandem Repeat Analysis for Rapid and Accurate Typing of Virulent Multidrug Resistant Escherichia coli Clones

PLoS ONE, 2012

One hundred E. coli isolates from Norway (n = 37), Sweden (n = 24), UK (n = 20) and Spain (n = 19... more One hundred E. coli isolates from Norway (n = 37), Sweden (n = 24), UK (n = 20) and Spain (n = 19), producing CTX-M-type - (n = 84), or SHV-12 (n = 4) extended spectrum β-lactamases, or the plasmid mediated AmpC, CMY-2 (n = 12), were typed using multi-locus sequence typing (MLST) and multi-locus variable number of tandem repeat analysis (MLVA). Isolates clustered into 33 Sequence Types (STs) and 14 Sequence Type Complexes (STCs), and 58 MLVA-Types (MTs) and 25 different MLVA-Type Complexes (MTCs). A strong agreement between the MLST profile and MLVA typing results was observed, in which all ST131-isolates (n = 39) and most of the STC-648 (n = 10), STC-38 (n = 9), STC-10 (n = 9), STC-405 (n = 8) and STC-23 (n = 6) isolates were clustered distinctly into MTC-29, -36, -20, -14, -10 and -39, respectively. MLVA is a rapid and accurate tool for genotyping isolates of globally disseminated virulent multidrug resistant E. coli lineages, including ST131.

Research paper thumbnail of Persistence of a pKPN3-Like CTX-M-15-Encoding IncFIIK Plasmid in a Klebsiella pneumonia ST17 Host during Two Years of Intestinal Colonization

PloS one, 2015

To characterize the CTX-M-15-encoding plasmid in a Klebsiella pneumoniae ST17 strain, responsible... more To characterize the CTX-M-15-encoding plasmid in a Klebsiella pneumoniae ST17 strain, responsible for an outbreak at a Norwegian neonatal intensive care unit and subsequent colonization of affected children for up to two years. To identify plasmid-mediated features relevant for the outbreak dynamics, and to investigate the plasmids capability of horizontal transfer, its segregational stability and plasmid-mediated fitness costs. Plasmid profiling was performed by S1-nuclease PFGE, PCR-based replicon typing and Southern blot-hybridization. The complete sequence of the CTX-M-15-encoding plasmid was obtained by 454 sequencing. Plasmid self-transferability was investigated by broth- and filter mating, segregational stability was explored by serial passage, and plasmid-conferred fitness costs were examined in pairwise head-to-head competitions and by growth rate comparisons. CTX-M-15 was encoded by a ~180 kb IncFIIK plasmid in K. pneumoniae ST17. S1-nuclease PFGE profiles of the first an...

Research paper thumbnail of Extended-spectrum beta-lactamase-producing bacteria are not detected in supragingival plaque samples from human fecal carriers of ESBL-producing Enterobacteriaceae

Journal of oral microbiology, 2014

The prevalence of infections caused by Cefotaximase-Munich (CTX-M)-type extended-spectrum beta-la... more The prevalence of infections caused by Cefotaximase-Munich (CTX-M)-type extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBL-E) has rapidly increased during the past 15 years. Enterobacteriaceae are commonly found in the gastrointestinal tract and long-term intestinal carriage is considered important for the spread of ESBL and as a source of clinical infections. Oral biofilm such as supragingival plaque is known to contain numerous antibiotic resistance determinants and may also represent a poorly investigated site for ESBL carriage and further spread. To investigate possible carriage of ESBL-producing bacteria in supragingival plaque of known fecal carriers of these bacteria. We screened for the presence of aerobic and anaerobic ESBL-producing bacteria and bla CTX-M in supragingival plaque samples from healthy human adults with culture-verified fecal carriage of CTX-M-producing Escherichia coli. The presence or absence of Enterobacteriaceae and ESBL-producing bacteri...

Research paper thumbnail of Transferable vanB2 Tn5382-containing elements in fecal streptococcal strains from veal calves

Antimicrobial agents and chemotherapy, 2003

Three vancomycin-resistant veal calf fecal streptococci, identified as Streptococcus gallolyticus... more Three vancomycin-resistant veal calf fecal streptococci, identified as Streptococcus gallolyticus (n = 2) and Streptococcus lutetiensis, were shown to harbor vanB2 Tn5382-like elements earlier described in enterococci. One S. gallolyticus strain had a 1,495-bp IS256-related element inserted in vanS(B). The vanB2 Tn5382 element present in the plasmid-free S. lutetiensis strain was transferable to Enterococcus faecium BM4105-RF, Enterococcus faecalis JH2-2, and its recombination-deficient derivative, UV202. The transfer frequencies were comparable between recipient strains (from 1 x 10(-7) to 7 x 10(-6)). All transconjugants acquired a vanB-containing chromosomal insert of approximately 100 kb, apparently by site-specific integration. Secondary transconjugants were not observed in intraspecies retransfer experiments. These observations are consistent with a conjugative, selftransmissible, integrative element that might be involved in the interspecies spread of vanB2 resistance determi...

Research paper thumbnail of Nonconjugative transposition of the vanB-containing Tn5382-like element in Enterococcus faecium

Antimicrobial agents and chemotherapy, 2003

The vanB2 operon encoding glycopeptide resistance is an integral part of the putative conjugative... more The vanB2 operon encoding glycopeptide resistance is an integral part of the putative conjugative transposon Tn5382. Characterization of clinical glycopeptide resistant derivatives from an epidemic ampicillin-resistant Enterococcus faecium strain showed precise chromosomal or plasmid insertions of a vanB2-containing Tn5382-like element. Conjugative transposition of the Tn5382-like element was not demonstrated in retransfer studies.

Research paper thumbnail of Genetic methods for detection of antimicrobial resistance

Sundsfjord A, Simonsen GS, Haldorsen BC, Haaheim H, Hjelmevoll SO, Littauer P, Dahl KH. Genetic m... more Sundsfjord A, Simonsen GS, Haldorsen BC, Haaheim H, Hjelmevoll SO, Littauer P, Dahl KH. Genetic methods for detection of antimicrobial resistance. APMIS 2004;112:815-37.

Research paper thumbnail of Identification of VIM-2-Producing Pseudomonas aeruginosa from Tanzania Is Associated with Sequence Types 244 and 640 and the Location of bla VIM-2 in a TniC Integron: TABLE 1

Antimicrobial Agents and Chemotherapy, 2014

Running title (max 54 characters incl. spaces): VIM-2-producing P. aeruginosa from 16 Tanzania 17

Research paper thumbnail of Multilocus sequence typing and ftsI sequencing: a powerful tool for surveillance of penicillin-binding protein 3-mediated beta-lactam resistance in nontypeable Haemophilus influenzae

BMC Microbiology, 2014

Background: Beta-lactam resistance in Haemophilus influenzae due to ftsI mutations causing altere... more Background: Beta-lactam resistance in Haemophilus influenzae due to ftsI mutations causing altered penicillin-binding protein 3 (PBP3) is increasing worldwide. Low-level resistant isolates with the N526K substitution (group II low-rPBP3) predominate in most geographical regions, while high-level resistant isolates with the additional S385T substitution (group III high-rPBP3) are common in Japan and South Korea. Knowledge about the molecular epidemiology of rPBP3 strains is limited. We combined multilocus sequence typing (MLST) and ftsI/PBP3 typing to study the emergence and spread of rPBP3 in nontypeable H. influenzae (NTHi) in Norway. Results: The prevalence of rPBP3 in a population of 795 eye, ear and respiratory isolates (99% NTHi) from 2007 was 15%. The prevalence of clinical PBP3-mediated resistance to ampicillin was 9%, compared to 2.5% three years earlier. Group II low-rPBP3 predominated (96%), with significant proportions of isolates non-susceptible to cefotaxime (6%) and meropenem (20%). Group III high-rPBP3 was identified for the first time in Northern Europe. Four MLST sequence types (ST) with characteristic, highly diverging ftsI alleles accounted for 61% of the rPBP3 isolates. The most prevalent substitution pattern (PBP3 type A) was present in 41% of rPBP3 isolates, mainly carried by ST367 and ST14. Several unrelated STs possessed identical copies of the ftsI allele encoding PBP3 type A. Infection sites, age groups, hospitalization rates and rPBP3 frequencies differed between STs and phylogenetic groups.

Research paper thumbnail of Within-Population Distribution of Trimethoprim Resistance in Escherichia coli before and after a Community-Wide Intervention on Trimethoprim Use

A 2-year prospective intervention on the prescription of trimethoprim reduced the use by 85% in a... more A 2-year prospective intervention on the prescription of trimethoprim reduced the use by 85% in a health care region with 178,000 inhabitants. Here, we performed before-and-after analyses of the within-population distribution of trimethoprim resistance in Escherichia coli. Phylogenetic and population genetic methods were applied to multilocus sequence typing data of 548 consecutively collected E. coli isolates from clinical urinary specimens. Results were analyzed in relation to antibiotic susceptibility and the presence and genomic location of different trimethoprim resistance gene classes. A total of 163 E. coli sequence types (STs) were identified, of which 68 were previously undescribed. The isolates fell into one of three distinct genetic clusters designated BAPS 1 (E. coli phylogroup B2), BAPS 2 (phylogroup A and B1), and BAPS 3 (phylogroup D), each with a similar frequency before and after the intervention. BAPS 2 and BAPS 3 were positively and BAPS 1 was negatively associated with trimethoprim resistance . In before-and-after analyses, trimethoprim resistance frequency increased in BAPS 1 and decreased in BAPS 2. Resistance to antibiotics other than trimethoprim increased in BAPS 2. Analysis of the genomic location of different trimethoprim resistance genes in isolates of ST69, ST58, and ST73 identified multiple independent acquisition events in isolates of the same ST. The results show that despite a stable overall resistance frequency in E. coli before and after the intervention, marked within-population changes occurred. A decrease of resistance in one major genetic cluster was masked by a reciprocal increase in another major cluster.

Research paper thumbnail of Siste skanse for effektive antibiotika?

Tidsskrift for Den norske legeforening, 2012

Research paper thumbnail of Evaluation of the total MBL confirm kit (ROSCO) for detection of metallo-β-lactamases in Pseudomonas aeruginosa and Acinetobacter baumannii

Diagnostic microbiology and infectious disease, 2014

Phenotypic tests for carbapenemase production in Pseudomonas aeruginosa and Acinetobacter baumann... more Phenotypic tests for carbapenemase production in Pseudomonas aeruginosa and Acinetobacter baumannii have been associated with unspecific metallo-β-lactamase (MBL) inhibitor activity in synergy tests and low positive predictive value. In this study, a collection of well-characterized P. aeruginosa and A. baumannii isolates was used to evaluate the inhibitor-based Total MBL Confirm Kit and the MBL Etest.

Research paper thumbnail of A Multicentre Hospital Outbreak in Sweden Caused by Introduction of a vanB2 Transposon into a Stably Maintained pRUM-Plasmid in an Enterococcus faecium ST192 Clone

PLoS ONE, 2014

The clonal dissemination of VanB-type vancomycin-resistant Enterococcus faecium (VREfm) strains i... more The clonal dissemination of VanB-type vancomycin-resistant Enterococcus faecium (VREfm) strains in three Swedish hospitals between 2007 and 2011 prompted further analysis to reveal the possible origin and molecular characteristics of the outbreak strain. A representative subset of VREfm isolates (n = 18) and vancomycin-susceptible E. faecium (VSEfm, n = 2) reflecting the spread in time and location was approached by an array of methods including: selective whole genome sequencing (WGS; n = 3), multi locus sequence typing (MLST), antimicrobial susceptibility testing, virulence gene profiling, identification of mobile genetic elements conferring glycopeptide resistance and their ability to support glycopeptide resistance transfer. In addition, a single VREfm strain with an unrelated PFGE pattern collected prior to the outbreak was examined by WGS. MLST revealed a predominance of ST192, belonging to a hospital adapted high-risk lineage harbouring several known virulence determinants (n$10). The VREfm outbreak strain was resistant to ampicillin, gentamicin, ciprofloxacin and vancomycin, and susceptible to teicoplanin. Consistently, a vanB2-subtype as part of Tn1549/Tn5382 with a unique genetic signature was identified in the VREfm outbreak strains. Moreover, Southern blot hybridisation analyses of PFGE separated S1 nuclease-restricted total DNAs and filter mating experiments showed that vanB2-Tn1549/Tn5382 was located in a 70-kb sized rep 17/pRUM plasmid readily transferable between E. faecium. This plasmid contained an axe-txe toxinantitoxin module associated with stable maintenance. The two clonally related VSEfm harboured a 40 kb rep 17/pRUM plasmid absent of the 30 kb vanB2-Tn1549/Tn5382 gene complex. Otherwise, these two isolates were similar to the VREfm outbreak strain in virulence-and resistance profile. In conclusion, our observations support that the origin of the multicentre outbreak was caused by an introduction of vanB2-Tn1549/Tn5382 into a rep 17/pRUM plasmid harboured in a pre-existing high-risk E. faecium ST192 clone. The subsequent dissemination of VREfm to other centres was primarily caused by clonal spread rather than plasmid transfer to pre-existing high-risk clones. Citation: Sivertsen A, Billströ m H, Melefors Ö , Liljequist BO, Wisell KT, et al. (2014) A Multicentre Hospital Outbreak in Sweden Caused by Introduction of a vanB2 Transposon into a Stably Maintained pRUM-Plasmid in an Enterococcus faecium ST192 Clone. PLoS ONE 9(8): e103274.

Research paper thumbnail of Typeability of Tn 1546 -like Elements in Vancomycin-Resistant Enterococci Using Long-Range PCRs and Specific Analysis of Polymorphic Regions

Microbial Drug Resistance, 2000

Molecular subtyping of the VanA-type resistance element Tn1546 in an international collection of ... more Molecular subtyping of the VanA-type resistance element Tn1546 in an international collection of 81 genomically diverse vancomycin-resistant enterococci (VRE) from human, animal, and environmental reservoirs was evaluated by restriction analysis of long-range PCR amplicons (PCR-RFLP), single gene PCRs, Southern blot analysis of genomic digests, and partial DNA sequencing. A dominant Tn1546-RFLP in accordance with Enterococcus faecium BM4147 was detected in 43 of the 49 long-range PCR positive strains from ecologically diverse sources in several European countries and the US. Tn1546-like elements from the 32 (40%) long-range PCR negative strains were typed into 17 different groups by single-gene PCRs and Southern blot analysis of the ORF1, ORF2, vanS-vanH, vanX-vanY, and vanZ regions. All these isolates showed deletions in the ORF1 and/or vanZ primer binding regions explaining the failure of long-range PCR amplification. Enlarged vanS-vanH or vanX-vanY fragments were detected in 7 (22%) and 16 (50%) of the long-range PCR negative strains, respectively. The enlarged vanS-vanH regions of five clinical isolates from the US (n = 2), Ireland (n = 2), and Norway (n = 1) contained identical IS1251-like insertions indicating intercontinental spread of the vanA gene cluster. Intergenic vanS-vanH IS1251 insertions have so far not been reported in European studies. Structural rearrangements of Tn1546-like elements may represent single recombination events that can serve as fingerprints in the molecular examination of vanA gene cluster evolution and transmission. The optimal strategy for such analysis has yet to be determined. Two alternative long-range PCRs with subsequent RFLP analysis were successfully used to type the majority of vanA gene clusters in an ecologically and geographically heterogeneous VRE strain collection, but failed to detect and type a group of variant Tn1546-like elements truncated in the left-end ORF1/ORF2 region. Further subtyping of such variants should specifically target the polymorphic vanS-vanH and vanX-vanY regions.

Research paper thumbnail of Effects of Phenotype and Genotype on Methods for Detection of Extended-Spectrum--Lactamase-Producing Clinical Isolates of Escherichia coli and Klebsiella pneumoniae in Norway

Escherichia coli (n ‫؍‬ 87) and Klebsiella pneumoniae (n ‫؍‬ 25) with reduced susceptibilities to... more Escherichia coli (n ‫؍‬ 87) and Klebsiella pneumoniae (n ‫؍‬ 25) with reduced susceptibilities to oxyimino-cephalosporins (MICs > 1 mg/liter) from 18 Norwegian laboratories during March through October 2003 were examined for bla TEM/SHV/CTX-M extended-spectrum-␤-lactamase (ESBL) genes, oxyimino-cephalosporin MIC profiles, ESBL phenotypes (determined by the ESBL Etest and the combined disk and double-disk synergy [DDS] methods), and susceptibility to non-␤-lactam antibiotics. Multidrugresistant CTX-M-15-like (n ‫؍‬ 23) and CTX-M-9-like (n ‫؍‬ 15) ESBLs dominated among the 50 ESBL-positive E. coli isolates. SHV-5-like (n ‫؍‬ 9) and SHV-2-like (n ‫؍‬ 4) ESBLs were the most prevalent in 19 ESBL-positive K. pneumoniae isolates. Discrepant ESBL phenotype test results were observed for one major (CTX-M-9) and several minor (TEM-128 and SHV-2/-28) ESBL groups and in SHV-1/-11-hyperproducing isolates. Negative or borderline ESBL results were observed when low-MIC oxyimino-cephalosporin substrates were used to detect clavulanic acid (CLA) synergy. CLA synergy was detected by the ESBL Etest and the DDS method but not by the combined disk method in SHV-1/-11-hyperproducing strains. The DDS method revealed unexplained CLA synergy in combination with aztreonam and cefpirome in three E. coli strains. The relatively high proportion of ESBL-producing E. coli organisms with a low ceftazidime MIC in Norway emphasizes that cefpodoxime alone or both cefotaxime and ceftazidime should be used as substrates for ESBL detection.

Research paper thumbnail of Peripheral Facial Palsy and Coincidental Cytomegalovirus Infection or Reactivation

Scandinavian Journal of Infectious Diseases, 1983

Following the fortuitous demonstration of anti-cytomegalovirus (CMV) IgM antibodies in serum samp... more Following the fortuitous demonstration of anti-cytomegalovirus (CMV) IgM antibodies in serum samples from 2 patients with acute peripheral facial palsy (APFP), a systematic study was initiated which provided serological evidence of a coincidental CMV multiplication in 72% of 65 consecutive cases with APFP. Transmission electron microscopy has revealed Herpetoviridae-like virus particles in 56% of urine samples studied. A reactivation of latent CMV at the time of palsy onset is considered the most probable explanation of these findings.

Research paper thumbnail of Antibodies to Eukaryotic, including Autologous, Native DNA are Produced during BK Virus Infection, but not after Immunization with NonInfectious BK DNA

Scandinavian Journal of Immunology, 1992

The contemporary view concerning the origin of anti-dsDNA antibodies is that eukaryotic dsDNA is ... more The contemporary view concerning the origin of anti-dsDNA antibodies is that eukaryotic dsDNA is not immunogenic. Results presented here, however, show (1) that inoculation of rabbits with BK virus elicits antibodies to eukaryotic, including autologous, dsDNA. (2) that the transition from a non-immunogenic to an immunogenic state of autologous dsDNA depends on productive infection with BK virus, and (3) that inoculation with protein-free circular BK dsDNA initiates both infection in vivo and production of antibodies to autologous dsDNA. Non-infectious linearized BK dsDNA did not elicit any anti-dsDNA antibodies, while the same DNA molecule, when complexed with methylated bovine serum albumin, elicited anti-dsDNA antibodies solely recognizing BK dsDNA. Neither of the two linearized BK dsDNA preparations initiated infection. Using two different techniques, we could demonstrate that two separate sets of anti-dsDNA antibodies were produced during viral infection; one recognizing BK dsDNA, and the other recognizing autologous dsDNA. Thus, in contrast to previous assumptions, autologous dsDNA may be immunogenic. Based on the present results, we propose that autologous dsDNA can be rendered immunogenic through complex formation with viral DNA binding protein(s) such as the structural protein VP1 or the tumour antigen T. Such DNA protein complexes may bypass a pulative T-cell tolerance to autologous dsDNA.

Research paper thumbnail of P871 Phenotypic detection of AmpC in E. coli: comparison of cloxacillin, boronic acid and EDTA disk synergy assays

International Journal of Antimicrobial Agents - INT J ANTIMICROBIAL AGENTS, 2007

The antibiotics MICs value were determined by agar dilution methods, according to CLSI recommenda... more The antibiotics MICs value were determined by agar dilution methods, according to CLSI recommendation. The presence of class 1 integron and genes coding ESBL-type enzymes among P. aeruginosa was detected by PCR. Gene cassettes were identified by sequencing of the obtained amplicons. Results: The ESBL-type enzymes were detected among 12 strains, by double-discs synergy test with inhibitors of serine b-lactamases. However, this test showed to be not useful for detection of ESBLs in the remaining 23 isolates. Three out of 23 strains were resistant to all b-lactams. In 2 isolates the gene coding class A b-lactamases was identified -blaGES-1 in a strain from hospital A and blaTEM-1-like in a strain received from hospital B. The clinical isolate producing GES-1 exhibited the inhibitor-sensitive phenotype. The synergy pattern between inhibitors (clavulanic acid or imipenem) and ceftazidime, cefepime or aztreonam was observed, as well as resistance to gentamicin and all b-lactams except imipenem. The gene blaGES-1 is located on the variable region of class 1 integron. The other strain, producing TEM-1-like enzyme, was resistant to all b-lactams and no synergy between inhibitors and b-lactams was observed. Additionally in case of this strain no VIM-type metallo-enzymes were found. Conclusion: GES-1 and TEM-1-like b-lactamases producing P. aeruginosa strains were identified the first time in Poland. The double-discs synergy test was not useful for detection of all Ambler class A ESBLs among P. aeruginosa isolates.

Research paper thumbnail of Risk factors for acquisition of CTX-M-15 extended-spectrum beta-lactamase-producing Klebsiella pneumoniae during an outbreak in a neonatal intensive care unit in Norway

Scandinavian Journal of Infectious Diseases, 2013

Background: A CTX-M-15 extended-spectrum beta-lactamase (ESBL)-producing Klebsiella pneumoniae wa... more Background: A CTX-M-15 extended-spectrum beta-lactamase (ESBL)-producing Klebsiella pneumoniae was responsible for an outbreak in the neonatal intensive care unit (NICU) at Stavanger University Hospital, Norway over a 5-month period (November 2008 -April 2009. The risk factors for acquiring ESBL-producing K. pneumoniae during the outbreak were examined in this study. Methods: Faecal or rectal cultures were obtained from infants hospitalized in the NICU during the outbreak period and examined for ESBL-producing K. pneumoniae. Data were retrospectively retrieved from the medical records, including sex, gestational age, birth weight, indwelling central vascular catheter, continuous positive airway pressure (CPAP), mechanical ventilation, parenteral nutrition, antibiotic treatment, mode of delivery (vaginal vs caesarean), length of hospital stay, and mortality. Results: A total of 216 infants were hospitalized in the NICU during the outbreak period, of whom 212 were screened; 51 (24%) scored positive for faecal colonization with ESBL-producing K. pneumoniae. One infant acquired a clinical infection. Forty-four colonized infants and 55 non-colonized infants were included in the risk analysis. Colonized infants had a lower birth weight, lower gestational age, and a longer hospital stay compared to noncolonized infants. By logistic regression, prematurity (gestational age Ͻ 37 weeks) and treatment with antibiotics were independent risk factors for acquiring ESBL-producing K. pneumoniae in the fi nal model. Conclusion: Prematurity and treatment with antibiotics were independent risk factors for colonization during this NICU outbreak with ESBL-producing K. pneumoniae.

Research paper thumbnail of Intrahospital Spread of Vancomycin-resistant Enterococcus faecium in Sweden

Scandinavian Journal of Infectious Diseases, 1997

ABSTRACT

Research paper thumbnail of Investigating the mobilome in clinically important lineages of Enterococcus faecium and Enterococcus faecalis

BMC genomics, Jan 10, 2015

The success of Enterococcus faecium and E. faecalis evolving as multi-resistant nosocomial pathog... more The success of Enterococcus faecium and E. faecalis evolving as multi-resistant nosocomial pathogens is associated with their ability to acquire and share adaptive traits, including antimicrobial resistance genes encoded by mobile genetic elements (MGE). Here, we investigate this mobilome in successful hospital associated genetic lineages, E. faecium sequence type (ST)17 (n=10) and ST78 (n=10), E. faecalis ST6 (n=10) and ST40 (n=10) by DNA microarray analyses. The hybridization patterns of 272 representative targets including plasmid backbones (n=85), transposable elements (n=85), resistance determinants (n=67), prophages (n=29), and clustered regularly interspaced short palindromic repeats (CRISPR)-cas sequences (n=6) separated the strains according to species, and for E. faecalis also according to STs. RCR-, Rep_3-, RepA_N- and Inc18-family plasmids were highly prevalent and with the exception of Rep_3, evenly distributed between the species. There was a considerable difference in...

Research paper thumbnail of Multi-Locus Variable Number of Tandem Repeat Analysis for Rapid and Accurate Typing of Virulent Multidrug Resistant Escherichia coli Clones

PLoS ONE, 2012

One hundred E. coli isolates from Norway (n = 37), Sweden (n = 24), UK (n = 20) and Spain (n = 19... more One hundred E. coli isolates from Norway (n = 37), Sweden (n = 24), UK (n = 20) and Spain (n = 19), producing CTX-M-type - (n = 84), or SHV-12 (n = 4) extended spectrum β-lactamases, or the plasmid mediated AmpC, CMY-2 (n = 12), were typed using multi-locus sequence typing (MLST) and multi-locus variable number of tandem repeat analysis (MLVA). Isolates clustered into 33 Sequence Types (STs) and 14 Sequence Type Complexes (STCs), and 58 MLVA-Types (MTs) and 25 different MLVA-Type Complexes (MTCs). A strong agreement between the MLST profile and MLVA typing results was observed, in which all ST131-isolates (n = 39) and most of the STC-648 (n = 10), STC-38 (n = 9), STC-10 (n = 9), STC-405 (n = 8) and STC-23 (n = 6) isolates were clustered distinctly into MTC-29, -36, -20, -14, -10 and -39, respectively. MLVA is a rapid and accurate tool for genotyping isolates of globally disseminated virulent multidrug resistant E. coli lineages, including ST131.

Research paper thumbnail of Persistence of a pKPN3-Like CTX-M-15-Encoding IncFIIK Plasmid in a Klebsiella pneumonia ST17 Host during Two Years of Intestinal Colonization

PloS one, 2015

To characterize the CTX-M-15-encoding plasmid in a Klebsiella pneumoniae ST17 strain, responsible... more To characterize the CTX-M-15-encoding plasmid in a Klebsiella pneumoniae ST17 strain, responsible for an outbreak at a Norwegian neonatal intensive care unit and subsequent colonization of affected children for up to two years. To identify plasmid-mediated features relevant for the outbreak dynamics, and to investigate the plasmids capability of horizontal transfer, its segregational stability and plasmid-mediated fitness costs. Plasmid profiling was performed by S1-nuclease PFGE, PCR-based replicon typing and Southern blot-hybridization. The complete sequence of the CTX-M-15-encoding plasmid was obtained by 454 sequencing. Plasmid self-transferability was investigated by broth- and filter mating, segregational stability was explored by serial passage, and plasmid-conferred fitness costs were examined in pairwise head-to-head competitions and by growth rate comparisons. CTX-M-15 was encoded by a ~180 kb IncFIIK plasmid in K. pneumoniae ST17. S1-nuclease PFGE profiles of the first an...

Research paper thumbnail of Extended-spectrum beta-lactamase-producing bacteria are not detected in supragingival plaque samples from human fecal carriers of ESBL-producing Enterobacteriaceae

Journal of oral microbiology, 2014

The prevalence of infections caused by Cefotaximase-Munich (CTX-M)-type extended-spectrum beta-la... more The prevalence of infections caused by Cefotaximase-Munich (CTX-M)-type extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBL-E) has rapidly increased during the past 15 years. Enterobacteriaceae are commonly found in the gastrointestinal tract and long-term intestinal carriage is considered important for the spread of ESBL and as a source of clinical infections. Oral biofilm such as supragingival plaque is known to contain numerous antibiotic resistance determinants and may also represent a poorly investigated site for ESBL carriage and further spread. To investigate possible carriage of ESBL-producing bacteria in supragingival plaque of known fecal carriers of these bacteria. We screened for the presence of aerobic and anaerobic ESBL-producing bacteria and bla CTX-M in supragingival plaque samples from healthy human adults with culture-verified fecal carriage of CTX-M-producing Escherichia coli. The presence or absence of Enterobacteriaceae and ESBL-producing bacteri...

Research paper thumbnail of Transferable vanB2 Tn5382-containing elements in fecal streptococcal strains from veal calves

Antimicrobial agents and chemotherapy, 2003

Three vancomycin-resistant veal calf fecal streptococci, identified as Streptococcus gallolyticus... more Three vancomycin-resistant veal calf fecal streptococci, identified as Streptococcus gallolyticus (n = 2) and Streptococcus lutetiensis, were shown to harbor vanB2 Tn5382-like elements earlier described in enterococci. One S. gallolyticus strain had a 1,495-bp IS256-related element inserted in vanS(B). The vanB2 Tn5382 element present in the plasmid-free S. lutetiensis strain was transferable to Enterococcus faecium BM4105-RF, Enterococcus faecalis JH2-2, and its recombination-deficient derivative, UV202. The transfer frequencies were comparable between recipient strains (from 1 x 10(-7) to 7 x 10(-6)). All transconjugants acquired a vanB-containing chromosomal insert of approximately 100 kb, apparently by site-specific integration. Secondary transconjugants were not observed in intraspecies retransfer experiments. These observations are consistent with a conjugative, selftransmissible, integrative element that might be involved in the interspecies spread of vanB2 resistance determi...

Research paper thumbnail of Nonconjugative transposition of the vanB-containing Tn5382-like element in Enterococcus faecium

Antimicrobial agents and chemotherapy, 2003

The vanB2 operon encoding glycopeptide resistance is an integral part of the putative conjugative... more The vanB2 operon encoding glycopeptide resistance is an integral part of the putative conjugative transposon Tn5382. Characterization of clinical glycopeptide resistant derivatives from an epidemic ampicillin-resistant Enterococcus faecium strain showed precise chromosomal or plasmid insertions of a vanB2-containing Tn5382-like element. Conjugative transposition of the Tn5382-like element was not demonstrated in retransfer studies.

Research paper thumbnail of Genetic methods for detection of antimicrobial resistance

Sundsfjord A, Simonsen GS, Haldorsen BC, Haaheim H, Hjelmevoll SO, Littauer P, Dahl KH. Genetic m... more Sundsfjord A, Simonsen GS, Haldorsen BC, Haaheim H, Hjelmevoll SO, Littauer P, Dahl KH. Genetic methods for detection of antimicrobial resistance. APMIS 2004;112:815-37.

Research paper thumbnail of Identification of VIM-2-Producing Pseudomonas aeruginosa from Tanzania Is Associated with Sequence Types 244 and 640 and the Location of bla VIM-2 in a TniC Integron: TABLE 1

Antimicrobial Agents and Chemotherapy, 2014

Running title (max 54 characters incl. spaces): VIM-2-producing P. aeruginosa from 16 Tanzania 17

Research paper thumbnail of Multilocus sequence typing and ftsI sequencing: a powerful tool for surveillance of penicillin-binding protein 3-mediated beta-lactam resistance in nontypeable Haemophilus influenzae

BMC Microbiology, 2014

Background: Beta-lactam resistance in Haemophilus influenzae due to ftsI mutations causing altere... more Background: Beta-lactam resistance in Haemophilus influenzae due to ftsI mutations causing altered penicillin-binding protein 3 (PBP3) is increasing worldwide. Low-level resistant isolates with the N526K substitution (group II low-rPBP3) predominate in most geographical regions, while high-level resistant isolates with the additional S385T substitution (group III high-rPBP3) are common in Japan and South Korea. Knowledge about the molecular epidemiology of rPBP3 strains is limited. We combined multilocus sequence typing (MLST) and ftsI/PBP3 typing to study the emergence and spread of rPBP3 in nontypeable H. influenzae (NTHi) in Norway. Results: The prevalence of rPBP3 in a population of 795 eye, ear and respiratory isolates (99% NTHi) from 2007 was 15%. The prevalence of clinical PBP3-mediated resistance to ampicillin was 9%, compared to 2.5% three years earlier. Group II low-rPBP3 predominated (96%), with significant proportions of isolates non-susceptible to cefotaxime (6%) and meropenem (20%). Group III high-rPBP3 was identified for the first time in Northern Europe. Four MLST sequence types (ST) with characteristic, highly diverging ftsI alleles accounted for 61% of the rPBP3 isolates. The most prevalent substitution pattern (PBP3 type A) was present in 41% of rPBP3 isolates, mainly carried by ST367 and ST14. Several unrelated STs possessed identical copies of the ftsI allele encoding PBP3 type A. Infection sites, age groups, hospitalization rates and rPBP3 frequencies differed between STs and phylogenetic groups.

Research paper thumbnail of Within-Population Distribution of Trimethoprim Resistance in Escherichia coli before and after a Community-Wide Intervention on Trimethoprim Use

A 2-year prospective intervention on the prescription of trimethoprim reduced the use by 85% in a... more A 2-year prospective intervention on the prescription of trimethoprim reduced the use by 85% in a health care region with 178,000 inhabitants. Here, we performed before-and-after analyses of the within-population distribution of trimethoprim resistance in Escherichia coli. Phylogenetic and population genetic methods were applied to multilocus sequence typing data of 548 consecutively collected E. coli isolates from clinical urinary specimens. Results were analyzed in relation to antibiotic susceptibility and the presence and genomic location of different trimethoprim resistance gene classes. A total of 163 E. coli sequence types (STs) were identified, of which 68 were previously undescribed. The isolates fell into one of three distinct genetic clusters designated BAPS 1 (E. coli phylogroup B2), BAPS 2 (phylogroup A and B1), and BAPS 3 (phylogroup D), each with a similar frequency before and after the intervention. BAPS 2 and BAPS 3 were positively and BAPS 1 was negatively associated with trimethoprim resistance . In before-and-after analyses, trimethoprim resistance frequency increased in BAPS 1 and decreased in BAPS 2. Resistance to antibiotics other than trimethoprim increased in BAPS 2. Analysis of the genomic location of different trimethoprim resistance genes in isolates of ST69, ST58, and ST73 identified multiple independent acquisition events in isolates of the same ST. The results show that despite a stable overall resistance frequency in E. coli before and after the intervention, marked within-population changes occurred. A decrease of resistance in one major genetic cluster was masked by a reciprocal increase in another major cluster.

Research paper thumbnail of Siste skanse for effektive antibiotika?

Tidsskrift for Den norske legeforening, 2012

Research paper thumbnail of Evaluation of the total MBL confirm kit (ROSCO) for detection of metallo-β-lactamases in Pseudomonas aeruginosa and Acinetobacter baumannii

Diagnostic microbiology and infectious disease, 2014

Phenotypic tests for carbapenemase production in Pseudomonas aeruginosa and Acinetobacter baumann... more Phenotypic tests for carbapenemase production in Pseudomonas aeruginosa and Acinetobacter baumannii have been associated with unspecific metallo-β-lactamase (MBL) inhibitor activity in synergy tests and low positive predictive value. In this study, a collection of well-characterized P. aeruginosa and A. baumannii isolates was used to evaluate the inhibitor-based Total MBL Confirm Kit and the MBL Etest.

Research paper thumbnail of A Multicentre Hospital Outbreak in Sweden Caused by Introduction of a vanB2 Transposon into a Stably Maintained pRUM-Plasmid in an Enterococcus faecium ST192 Clone

PLoS ONE, 2014

The clonal dissemination of VanB-type vancomycin-resistant Enterococcus faecium (VREfm) strains i... more The clonal dissemination of VanB-type vancomycin-resistant Enterococcus faecium (VREfm) strains in three Swedish hospitals between 2007 and 2011 prompted further analysis to reveal the possible origin and molecular characteristics of the outbreak strain. A representative subset of VREfm isolates (n = 18) and vancomycin-susceptible E. faecium (VSEfm, n = 2) reflecting the spread in time and location was approached by an array of methods including: selective whole genome sequencing (WGS; n = 3), multi locus sequence typing (MLST), antimicrobial susceptibility testing, virulence gene profiling, identification of mobile genetic elements conferring glycopeptide resistance and their ability to support glycopeptide resistance transfer. In addition, a single VREfm strain with an unrelated PFGE pattern collected prior to the outbreak was examined by WGS. MLST revealed a predominance of ST192, belonging to a hospital adapted high-risk lineage harbouring several known virulence determinants (n$10). The VREfm outbreak strain was resistant to ampicillin, gentamicin, ciprofloxacin and vancomycin, and susceptible to teicoplanin. Consistently, a vanB2-subtype as part of Tn1549/Tn5382 with a unique genetic signature was identified in the VREfm outbreak strains. Moreover, Southern blot hybridisation analyses of PFGE separated S1 nuclease-restricted total DNAs and filter mating experiments showed that vanB2-Tn1549/Tn5382 was located in a 70-kb sized rep 17/pRUM plasmid readily transferable between E. faecium. This plasmid contained an axe-txe toxinantitoxin module associated with stable maintenance. The two clonally related VSEfm harboured a 40 kb rep 17/pRUM plasmid absent of the 30 kb vanB2-Tn1549/Tn5382 gene complex. Otherwise, these two isolates were similar to the VREfm outbreak strain in virulence-and resistance profile. In conclusion, our observations support that the origin of the multicentre outbreak was caused by an introduction of vanB2-Tn1549/Tn5382 into a rep 17/pRUM plasmid harboured in a pre-existing high-risk E. faecium ST192 clone. The subsequent dissemination of VREfm to other centres was primarily caused by clonal spread rather than plasmid transfer to pre-existing high-risk clones. Citation: Sivertsen A, Billströ m H, Melefors Ö , Liljequist BO, Wisell KT, et al. (2014) A Multicentre Hospital Outbreak in Sweden Caused by Introduction of a vanB2 Transposon into a Stably Maintained pRUM-Plasmid in an Enterococcus faecium ST192 Clone. PLoS ONE 9(8): e103274.

Research paper thumbnail of Typeability of Tn 1546 -like Elements in Vancomycin-Resistant Enterococci Using Long-Range PCRs and Specific Analysis of Polymorphic Regions

Microbial Drug Resistance, 2000

Molecular subtyping of the VanA-type resistance element Tn1546 in an international collection of ... more Molecular subtyping of the VanA-type resistance element Tn1546 in an international collection of 81 genomically diverse vancomycin-resistant enterococci (VRE) from human, animal, and environmental reservoirs was evaluated by restriction analysis of long-range PCR amplicons (PCR-RFLP), single gene PCRs, Southern blot analysis of genomic digests, and partial DNA sequencing. A dominant Tn1546-RFLP in accordance with Enterococcus faecium BM4147 was detected in 43 of the 49 long-range PCR positive strains from ecologically diverse sources in several European countries and the US. Tn1546-like elements from the 32 (40%) long-range PCR negative strains were typed into 17 different groups by single-gene PCRs and Southern blot analysis of the ORF1, ORF2, vanS-vanH, vanX-vanY, and vanZ regions. All these isolates showed deletions in the ORF1 and/or vanZ primer binding regions explaining the failure of long-range PCR amplification. Enlarged vanS-vanH or vanX-vanY fragments were detected in 7 (22%) and 16 (50%) of the long-range PCR negative strains, respectively. The enlarged vanS-vanH regions of five clinical isolates from the US (n = 2), Ireland (n = 2), and Norway (n = 1) contained identical IS1251-like insertions indicating intercontinental spread of the vanA gene cluster. Intergenic vanS-vanH IS1251 insertions have so far not been reported in European studies. Structural rearrangements of Tn1546-like elements may represent single recombination events that can serve as fingerprints in the molecular examination of vanA gene cluster evolution and transmission. The optimal strategy for such analysis has yet to be determined. Two alternative long-range PCRs with subsequent RFLP analysis were successfully used to type the majority of vanA gene clusters in an ecologically and geographically heterogeneous VRE strain collection, but failed to detect and type a group of variant Tn1546-like elements truncated in the left-end ORF1/ORF2 region. Further subtyping of such variants should specifically target the polymorphic vanS-vanH and vanX-vanY regions.

Research paper thumbnail of Effects of Phenotype and Genotype on Methods for Detection of Extended-Spectrum--Lactamase-Producing Clinical Isolates of Escherichia coli and Klebsiella pneumoniae in Norway

Escherichia coli (n ‫؍‬ 87) and Klebsiella pneumoniae (n ‫؍‬ 25) with reduced susceptibilities to... more Escherichia coli (n ‫؍‬ 87) and Klebsiella pneumoniae (n ‫؍‬ 25) with reduced susceptibilities to oxyimino-cephalosporins (MICs > 1 mg/liter) from 18 Norwegian laboratories during March through October 2003 were examined for bla TEM/SHV/CTX-M extended-spectrum-␤-lactamase (ESBL) genes, oxyimino-cephalosporin MIC profiles, ESBL phenotypes (determined by the ESBL Etest and the combined disk and double-disk synergy [DDS] methods), and susceptibility to non-␤-lactam antibiotics. Multidrugresistant CTX-M-15-like (n ‫؍‬ 23) and CTX-M-9-like (n ‫؍‬ 15) ESBLs dominated among the 50 ESBL-positive E. coli isolates. SHV-5-like (n ‫؍‬ 9) and SHV-2-like (n ‫؍‬ 4) ESBLs were the most prevalent in 19 ESBL-positive K. pneumoniae isolates. Discrepant ESBL phenotype test results were observed for one major (CTX-M-9) and several minor (TEM-128 and SHV-2/-28) ESBL groups and in SHV-1/-11-hyperproducing isolates. Negative or borderline ESBL results were observed when low-MIC oxyimino-cephalosporin substrates were used to detect clavulanic acid (CLA) synergy. CLA synergy was detected by the ESBL Etest and the DDS method but not by the combined disk method in SHV-1/-11-hyperproducing strains. The DDS method revealed unexplained CLA synergy in combination with aztreonam and cefpirome in three E. coli strains. The relatively high proportion of ESBL-producing E. coli organisms with a low ceftazidime MIC in Norway emphasizes that cefpodoxime alone or both cefotaxime and ceftazidime should be used as substrates for ESBL detection.

Research paper thumbnail of Peripheral Facial Palsy and Coincidental Cytomegalovirus Infection or Reactivation

Scandinavian Journal of Infectious Diseases, 1983

Following the fortuitous demonstration of anti-cytomegalovirus (CMV) IgM antibodies in serum samp... more Following the fortuitous demonstration of anti-cytomegalovirus (CMV) IgM antibodies in serum samples from 2 patients with acute peripheral facial palsy (APFP), a systematic study was initiated which provided serological evidence of a coincidental CMV multiplication in 72% of 65 consecutive cases with APFP. Transmission electron microscopy has revealed Herpetoviridae-like virus particles in 56% of urine samples studied. A reactivation of latent CMV at the time of palsy onset is considered the most probable explanation of these findings.

Research paper thumbnail of Antibodies to Eukaryotic, including Autologous, Native DNA are Produced during BK Virus Infection, but not after Immunization with NonInfectious BK DNA

Scandinavian Journal of Immunology, 1992

The contemporary view concerning the origin of anti-dsDNA antibodies is that eukaryotic dsDNA is ... more The contemporary view concerning the origin of anti-dsDNA antibodies is that eukaryotic dsDNA is not immunogenic. Results presented here, however, show (1) that inoculation of rabbits with BK virus elicits antibodies to eukaryotic, including autologous, dsDNA. (2) that the transition from a non-immunogenic to an immunogenic state of autologous dsDNA depends on productive infection with BK virus, and (3) that inoculation with protein-free circular BK dsDNA initiates both infection in vivo and production of antibodies to autologous dsDNA. Non-infectious linearized BK dsDNA did not elicit any anti-dsDNA antibodies, while the same DNA molecule, when complexed with methylated bovine serum albumin, elicited anti-dsDNA antibodies solely recognizing BK dsDNA. Neither of the two linearized BK dsDNA preparations initiated infection. Using two different techniques, we could demonstrate that two separate sets of anti-dsDNA antibodies were produced during viral infection; one recognizing BK dsDNA, and the other recognizing autologous dsDNA. Thus, in contrast to previous assumptions, autologous dsDNA may be immunogenic. Based on the present results, we propose that autologous dsDNA can be rendered immunogenic through complex formation with viral DNA binding protein(s) such as the structural protein VP1 or the tumour antigen T. Such DNA protein complexes may bypass a pulative T-cell tolerance to autologous dsDNA.

Research paper thumbnail of P871 Phenotypic detection of AmpC in E. coli: comparison of cloxacillin, boronic acid and EDTA disk synergy assays

International Journal of Antimicrobial Agents - INT J ANTIMICROBIAL AGENTS, 2007

The antibiotics MICs value were determined by agar dilution methods, according to CLSI recommenda... more The antibiotics MICs value were determined by agar dilution methods, according to CLSI recommendation. The presence of class 1 integron and genes coding ESBL-type enzymes among P. aeruginosa was detected by PCR. Gene cassettes were identified by sequencing of the obtained amplicons. Results: The ESBL-type enzymes were detected among 12 strains, by double-discs synergy test with inhibitors of serine b-lactamases. However, this test showed to be not useful for detection of ESBLs in the remaining 23 isolates. Three out of 23 strains were resistant to all b-lactams. In 2 isolates the gene coding class A b-lactamases was identified -blaGES-1 in a strain from hospital A and blaTEM-1-like in a strain received from hospital B. The clinical isolate producing GES-1 exhibited the inhibitor-sensitive phenotype. The synergy pattern between inhibitors (clavulanic acid or imipenem) and ceftazidime, cefepime or aztreonam was observed, as well as resistance to gentamicin and all b-lactams except imipenem. The gene blaGES-1 is located on the variable region of class 1 integron. The other strain, producing TEM-1-like enzyme, was resistant to all b-lactams and no synergy between inhibitors and b-lactams was observed. Additionally in case of this strain no VIM-type metallo-enzymes were found. Conclusion: GES-1 and TEM-1-like b-lactamases producing P. aeruginosa strains were identified the first time in Poland. The double-discs synergy test was not useful for detection of all Ambler class A ESBLs among P. aeruginosa isolates.

Research paper thumbnail of Risk factors for acquisition of CTX-M-15 extended-spectrum beta-lactamase-producing Klebsiella pneumoniae during an outbreak in a neonatal intensive care unit in Norway

Scandinavian Journal of Infectious Diseases, 2013

Background: A CTX-M-15 extended-spectrum beta-lactamase (ESBL)-producing Klebsiella pneumoniae wa... more Background: A CTX-M-15 extended-spectrum beta-lactamase (ESBL)-producing Klebsiella pneumoniae was responsible for an outbreak in the neonatal intensive care unit (NICU) at Stavanger University Hospital, Norway over a 5-month period (November 2008 -April 2009. The risk factors for acquiring ESBL-producing K. pneumoniae during the outbreak were examined in this study. Methods: Faecal or rectal cultures were obtained from infants hospitalized in the NICU during the outbreak period and examined for ESBL-producing K. pneumoniae. Data were retrospectively retrieved from the medical records, including sex, gestational age, birth weight, indwelling central vascular catheter, continuous positive airway pressure (CPAP), mechanical ventilation, parenteral nutrition, antibiotic treatment, mode of delivery (vaginal vs caesarean), length of hospital stay, and mortality. Results: A total of 216 infants were hospitalized in the NICU during the outbreak period, of whom 212 were screened; 51 (24%) scored positive for faecal colonization with ESBL-producing K. pneumoniae. One infant acquired a clinical infection. Forty-four colonized infants and 55 non-colonized infants were included in the risk analysis. Colonized infants had a lower birth weight, lower gestational age, and a longer hospital stay compared to noncolonized infants. By logistic regression, prematurity (gestational age Ͻ 37 weeks) and treatment with antibiotics were independent risk factors for acquiring ESBL-producing K. pneumoniae in the fi nal model. Conclusion: Prematurity and treatment with antibiotics were independent risk factors for colonization during this NICU outbreak with ESBL-producing K. pneumoniae.

Research paper thumbnail of Intrahospital Spread of Vancomycin-resistant Enterococcus faecium in Sweden

Scandinavian Journal of Infectious Diseases, 1997

ABSTRACT