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Published ahead of print on June 9, 2005, doi:10.1164/rccm.200503-449OC
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American Journal of Respiratory and Critical Care Medicine Vol 172. pp. 636-642, (2005)
© 2005 American Thoracic Society
doi: 10.1164/rccm.200503-449OC

Original Article

Reinfection and Mixed Infection Cause Changing Mycobacterium tuberculosis Drug-Resistance Patterns

Annelies van Rie, Thomas C. Victor, Madalene Richardson, Rabia Johnson, Gian D. van der Spuy, Emma J. Murray, Nulda Beyers, Nico C. Gey van Pittius, Paul D. van Helden and Robin M. Warren

Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; Department of Science and Technology/National Research Founcation Center of Excellence in Biomedical Tuberculosis Research/Medical Research Council Center for Molecular and Cellular Biology, Department of Medical Biochemistry; and Desmond Tutu TB Center, Department of Pediatrics and Child Health, Faculty of Health Sciences, Stellenbosch University, South Africa

Correspondence and requests for reprints should be addressed to Robin M. Warren, Ph.D., DST/NRF Centre of Excellence in Biomedical Tuberculosis Research/MRC Centre for Molecular and Cellular Biology, Department of Medical Biochemistry, Faculty of Health Sciences, Stellenbosch University, P.O. Box 19063, Tygerberg, South Africa 7505. E-mail: rw1{at}sun.ac.za

Rationale: 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. Objectives: 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. Measurements and Main 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.

Key Words: drug resistance • mixed infections • Mycobacterium tuberculosis • reinfection




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