The pitfall of cohort isolation in an outbreak of linezolid-resistant, vancomycin-resistant enterococci
Authors: J. Jung, K. Park, S.-H. Shin, J.-Y. Lee, M.-N. Kim, S.-H. Kim
Journal: Clinical Microbiology and Infection (2019)

The emergence of linezolid resistance among vancomycin-resistant enterococci (VRE) is raising questions on the effectiveness of infection control measures from antimicrobial stewardship to contact precaution and environmental disinfection. Recently, we have experienced an outbreak of linezolid-resistant VRE (LRVRE) in haematology wards where VRE are endemic and we operate a designated cohort room for VRE. It has been concerning that cohort isolation of VRE patients may attribute to the transmission of LRVRE. Although a few outbreaks of LRVRE have emerged from acquisition of linezolid resistance by de novo mutations under antibiotic pressure or clonal transfer of linezolid-resistant strains [1Ntokou E. Stathopoulos C. Kristo I. Dimitroulia E. Labrou M. Vasdeki A. et al.Intensive care unit dissemination of multiple clones of linezolid-resistant Enterococcus faecalis and Enterococcus faecium.J Antimicrob Chemother. 2012; 67: 1819-1823Crossref PubMed Scopus (44) Google Scholar, 2O'Driscoll C. Murphy V. Doyle O. Wrenn C. Flynn A. O'Flaherty N. et al.First outbreak of linezolid-resistant vancomycin-resistant Enterococcus faecium in an Irish hospital, February to September 2014.J Hosp Infect. 2015; 91: 367-370Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar, 3Abbo L. Shukla B.S. Giles A. Aragon L. Jimenez A. Camargo J.F. et al.Linezolid and vancomycin-resistant Enterococcus faecium in solid organ transplant recipients: infection control and antimicrobial stewardship using whole genome sequencing.Clin Infect Dis. 2018; https://doi.org/10.1093/cid/ciy903Crossref Scopus (16) Google Scholar], but no relative contribution of each mechanism has been elucidated. Therefore, questions concerning antimicrobial stewardship, contact precautions, and environmental disinfection as strategies for preventing and controlling LRVRE outbreaks have not been answered. We aimed to identify effective strategies for controlling LRVRE outbreaks. Cases included all patients with LRVRE infection or colonization from April to August 2018 in haematology wards containing a total of 92 beds, with 15 single occupancy rooms and 19 multiple occupancy rooms including a five-bed VRE cohort room. Before detection of the outbreak, patients carrying VRE were isolated in single rooms or the cohort room, with contact precautions, if their clinical specimens yielded VRE. For infection control of the LRVRE outbreak, the LRVRE cases were moved to single rooms if they were multiple occupancy, and LRVRE surveillance cultures were carried out for patients who had shared the same room. LRVRE isolates were tested for linezolid resistance genes and typed as possible by pairing with linezolid-susceptible VRE (LSVRE) previously isolated, using multilocus sequence typing (MLST) and pulsed-field gel electrophoresis (PFGE). The study was approved by the ethics committee of the Asan Medical Centre (IRB No. 2019-0984) and the need for informed consent for this study was waived. During the outbreak, there were ten cases: eight had bacteraemia and two were rectal swab-only positive (Table 1). Of the ten LRVRE cases, eight had had LSVRE bacteraemia a median of 50 days (interquartile range (IQR) 15–61) earlier and were treated with linezolid for 20 days (median, IQR 10–34) before the isolation of LRVRE. Six patients acquired LRVRE during their stay in the VRE cohort room. The outbreak of LRVRE was resolved after the introduction of contact investigation, contact precaution with single room isolation and enforced environmental cleaning.Table 1Characteristics of patients with linezolid-resistant, vancomycin-resistant Enterococci (LRVRE) and microbiological characteristics of LRVREPatient No.Clinical characteristicsMicrobiologic characteristicsUnderlying diseaseFirst Specimen of LRVRE isolateSubsequent LRVRE bacteraemiaPrevious isolation of LSVRE (source)Previous use of linezolid (days)Stay in VRE cohort roomaWhen the LRVRE was detected.GenotypingMLSTPFGE pulsotypevanAG2576Tb23S rRNA mutation.cfroptrALSVRELRVRELSVRELRVRE1Relapsed B-ALL after alloHCTBloodYes (blood)35Yes(+)(+)(-)(-)ST981ST981AA2Relapsed ALLBloodNoNoNo(+)(+)(-)(-)N/AST17N/AB3Relapsed AMLRectal swabNoYes (blood)32Yes(+)(+)(-)(-)ST80ST80EC4CML, alloHCT recipientBloodYes (blood)16NocPatients 3 and 4 shared a room before admission to the VRE cohort room. Patient 4 developed LRVRE bacteraemia and then moved to the VRE cohort room.(+)(+)(-)(-)ST202ST80FC5ALLBloodYes (blood)38Yes(+)(+)(-)(-)N/AST981N/AH6ALLRectal swabYesYes (blood)21Yes(+)(+)(-)(-)ST192ST80GC7Relapsed AML after alloHCTRectal swabNoYes (blood)18YesN/AN/AN/AN/AN/AN/AN/AN/A8Relapsed AMLBloodNoNoNo(+)(+)(-)(-)N/AST981N/AA9Relapsed LBLAscitesYesYes (blood)12No(+)(+)(-)(-)ST17ST17KK10Severe AA, treated with cyclosporine and ATGRectal swabYesYes (blood)11Yes(+)(+)(-)(-)N/AST17N/AKMLST, multilocus sequence type; PFGE pulsed-field gel electrophoresis; LSVRE, linezolid-susceptible, vancomycin-resistant enterococci; LRVRE, linezolid-resistant, vancomycin-resistant Enterococci; N/A, non-available; ALL, acute lymphoblastic leukaemia; alloHCT, allogeneic hematopoietic stem cell transplantation; CML, chronic myeloid leukaemia; AML, acute myeloid leukaemia; LBL, lymphoblastic lymphoma; AA, aplastic anaemia; ATG, anti-thymocyte globulin.a When the LRVRE was detected.b 23S rRNA mutation.c Patients 3 and 4 shared a room before admission to the VRE cohort room. Patient 4 developed LRVRE bacteraemia and then moved to the VRE cohort room. Open table in a new tab MLST, multilocus sequence type; PFGE pulsed-field gel electrophoresis; LSVRE, linezolid-susceptible, vancomycin-resistant enterococci; LRVRE, linezolid-resistant, vancomycin-resistant Enterococci; N/A, non-available; ALL, acute lymphoblastic leukaemia; alloHCT, allogeneic hematopoietic stem cell transplantation; CML, chronic myeloid leukaemia; AML, acute myeloid leukaemia; LBL, lymphoblastic lymphoma; AA, aplastic anaemia; ATG, anti-thymocyte globulin. LRVRE isolates from nine patients, including the five paired with LSVRE, were available for molecular typing; all carried the vanA gene and had the G2576T mutation in 23S rRNA, and none harboured the cfr or optrA genes. Three ST types and five pulsotypes (A, B, C, H and K) were found among the nine LRVRE isolates, including three clusters (two As, three Cs and two Ks). Of the five pairs, only two had identical pulsotypes (patients 1 and 9), suggesting that the others had acquired separate VRE strains with de novo mutations in 23S rRNA. The three type C LRVRE were isolated from patients (patients 3, 4 and 6) who had occupied the cohort room within a 20-day period, suggesting clonal spread. Patients 3 and 4 had shared a room before admission to the cohort room, and patient 6 stayed in the cohort room together with patients 3. We found that multiclonal spread of LRVRE and de novo mutation under antibiotic selection pressure contributed to this outbreak. It appears that linezolid resistance was derived from de novo mutations at least in cases 1 and 9 because they had identical pulsotypes in LSVRE and LRVRE isolates. Findings that all the LRVRE isolates had 23S rRNA mutation and most of the patients had received linezolid before acquisition of LRVRE support de novo mutations. However, clonal spread through cross-contamination also played an important role because two patients had no histories of linezolid use and because of the existence of three pulsotypes clusters. Since six of our patients acquired LRVRE during stays in the VRE cohort room, and patients 3 and 6 had acquired LRVRE with discordant pulsotypes of LSVRE isolates in the cohort room, there is an issue whether the VRE cohort room is rational or not in the setting of high use of linezolid. Patients in a multiple occupancy or cohort room are clearly vulnerable to cross-contamination by organisms that can survive in tough environmental conditions for a long time [[4]Kramer A. Schwebke I. Kampf G. How long do nosocomial pathogens persist on inanimate surfaces? A systematic review.BMC Infect Dis. 2006; 6: 130Crossref PubMed Scopus (1570) Google Scholar]. We suggest that patients with LRVRE should be placed in individual rooms or separated from those colonized with non-LRVRE, as they can transmit LRVRE to other patients. In addition, close monitoring for the emergence of LRVRE is needed in VRE patients who receive linezolid. In conclusion, both clonal spread of LRVRE and the acquisition of resistance mutations contributed to this outbreak. The use of cohort rooms and selective pressure from the use of linezolid are liable to spread LRVRE. This work was supported by a grant from Korean Society for Chemotherapy in 2018. All authors report no conflicts of interest relevant to this article. This study was presented in part in ECCMID 2019, 13-16 April, Amsterdam, Netherlands (Abstract number 2326).