title: Linezolid-resistant ST36 methicillin-resistant Staphylococcus aureus associated with prolonged linezolid treatment in two paediatric cystic fibrosis patients.
abstract: OBJECTIVE
  To describe the emergence of linezolid-resistant methicillin-resistant Staphylococcus aureus (MRSA) of sequence type (ST)36 lineage in two paediatric patients with cystic fibrosis, after long-term low-dose linezolid treatment.
  
  
  METHODS
  Two paediatric males with cystic fibrosis had sputum samples quantitatively cultured during hospitalization. After the isolation of MRSA from both patients, oral treatment with 300 mg linezolid twice daily was initiated for periods of 1-2 months separated by up to 6 months. Isolates cultured 9 months after the start of treatment were tested for resistance to linezolid by agar dilution (BSAC). Resistant isolates were examined for 23S rDNA mutations, and typed by phage and macrorestriction with SmaI. Isolates from follow-up sputum samples were obtained until 44-51 months after treatment with linezolid.
  
  
  RESULTS
  Colonization with MRSA was at a density of approximately 10(6) cfu/mL sputum for both subjects. Initial isolates were susceptible to linezolid, but, 9 months later, isolates from both patients were resistant (MICs > 16 mg/L). Both isolates were epidemic MRSA-16 variant A1 (ST36-MRSA-II), which is widespread in UK hospitals. Both isolates were heterozygous for a G2576T mutation in their 23S rDNA genes, but one was resistant to fusidic acid and tetracycline. In follow-up sampling, the younger patient yielded linezolid-resistant EMRSA-16 for a further 42 months, whilst the other lost the linezolid-resistant MRSA and had alternately Pseudomonas aeruginosa or linezolid-susceptible EMRSA-16 variant A1 isolated over 35 further months.
  
  
  CONCLUSIONS
  Linezolid resistance emerged in two isolates of ST36 MRSA colonizing the lungs of two paediatric cystic fibrosis patients. Subtherapeutic levels of linezolid may have facilitated the selection of resistance.
authors.affiliation: Centre for Infections, Health Protection Agency, 61 Colindale Avenue, London NW9 5EQ, UK. robert.hill@hpa.org.uk
authors.forename: Robert L R
authors.initials: RL
authors.lastname: Hill
authors.forename: Angela M
authors.initials: AM
authors.lastname: Kearns
authors.forename: James
authors.initials: J
authors.lastname: Nash
authors.forename: Sarah E
authors.initials: SE
authors.lastname: North
authors.forename: Rachel
authors.initials: R
authors.lastname: Pike
authors.forename: Timothy
authors.initials: T
authors.lastname: Newson
authors.forename: Neil
authors.initials: N
authors.lastname: Woodford
authors.forename: Richard
authors.initials: R
authors.lastname: Calver
authors.forename: David M
authors.initials: DM
authors.lastname: Livermore
mesh_terms: D000081:Acetamides / Q000627:therapeutic use*; D000293:Adolescent; D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D015373:Bacterial Typing Techniques; D001434:Bacteriophage Typing; D002648:Child; D003550:Cystic Fibrosis / Q000150:complications*; D016172:DNA Fingerprinting; D024881:Drug Resistance, Bacterial; D020459:Genes, rRNA; D006801:Humans; D000069349:Linezolid; D008297:Male; D055624:Methicillin-Resistant Staphylococcus aureus / Q000145:classification / Q000187:drug effects* / Q000235:genetics / Q000302:isolation & purification; D008826:Microbial Sensitivity Tests; D009154:Mutation; D023303:Oxazolidinones / Q000627:therapeutic use*; D012150:Polymorphism, Restriction Fragment Length; D011550:Pseudomonas aeruginosa / Q000302:isolation & purification; D012329:RNA, Bacterial / Q000235:genetics; D012338:RNA, Ribosomal, 23S / Q000235:genetics; D013183:Sputum / Q000382:microbiology; D013203:Staphylococcal Infections / Q000188:drug therapy* / Q000382:microbiology*; D006113:United Kingdom
chemical_list: D000081:Acetamides; D000900:Anti-Bacterial Agents; D023303:Oxazolidinones; D012329:RNA, Bacterial; D012338:RNA, Ribosomal, 23S; D000069349:Linezolid