title: Reinfection and mixed infection cause changing Mycobacterium tuberculosis drug-resistance patterns.
abstract: BACKGROUND
  Multiple infections with different strains of Mycobacterium tuberculosis may occur in settings where the infection pressure is high. The relevance of mixed infections for the patient, clinician, and control program remains unclear.
  
  
  OBJECTIVE
  This study aimed to describe reinfection and mixed infection as underlying mechanisms of changing drug-susceptibility patterns in serial sputum cultures.
  
  
  METHODS
  Serial M. tuberculosis sputum cultures from patients diagnosed with multi-drug-resistant (MDR) tuberculosis were evaluated by phenotypic drug-susceptibility testing and mutation detection methods. Genotypic analysis was done by IS6110 DNA fingerprinting and a novel strain-specific polymerase chain reaction amplification method.
  
  
  RESULTS
  DNA fingerprinting analysis of serial sputum cultures from 48 patients with MDR tuberculosis attributed 10 cases to reinfection and 1 case to mixed infection. In contrast, strain-specific polymerase chain reaction amplification analysis in 9 of the 11 cases demonstrated mixed infection in 5 cases, reinfection in 3 cases, and laboratory contamination in 1 case. Analysis of clinical data suggests that first-line therapy can select for a resistant subpopulation, whereas poor adherence or second-line therapy resulted in the reemergence of the drug-susceptible subpopulations.
  
  
  CONCLUSIONS
  We have shown that, in some patients with MDR tuberculosis, mixed infection may be responsible for observations attributed to reinfection by DNA fingerprinting. We conclude that treatment and adherence determines which strain is dominant. We hypothesize that treatment with second-line drugs may lead to reemergence of the drug-susceptible strain in patients with mixed infection.
authors.affiliation: Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: Annelies
authors.initials: A
authors.lastname: van Rie
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Victor
authors.forename: Madalene
authors.initials: M
authors.lastname: Richardson
authors.forename: Rabia
authors.initials: R
authors.lastname: Johnson
authors.forename: Gian D
authors.initials: GD
authors.lastname: van der Spuy
authors.forename: Emma J
authors.initials: EJ
authors.lastname: Murray
authors.forename: Nulda
authors.initials: N
authors.lastname: Beyers
authors.forename: Nico C
authors.initials: NC
authors.lastname: Gey van Pittius
authors.forename: Paul D
authors.initials: PD
authors.lastname: van Helden
authors.forename: Robin M
authors.initials: RM
authors.lastname: Warren
mesh_terms: D000995:Antitubercular Agents / Q000627:therapeutic use; D016172:DNA Fingerprinting; D004252:DNA Mutational Analysis; D024901:Drug Resistance, Multiple, Bacterial / Q000235:genetics*; D006801:Humans; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000235:genetics* / Q000302:isolation & purification; D012008:Recurrence; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy / Q000235:genetics* / Q000382:microbiology*
chemical_list: D000995:Antitubercular Agents