The rapid diagnosis of rifampin resistance is hampered by a reported insufficient specificity of molecular techniques for detection of rpoB mutations. Our objective for this study was to document the prevalence and prognostic value of rpoB mutations with unclear phenotypic resistance. The study design entailed sequencing directly from sputum of first failure or relapse patients without phenotypic selection and comparison of the standard retreatment regimen outcome, according to the mutation present. We found that among all rpoB mutations, the best-documented "disputed" rifampin resistance mutations (511Pro, 516Tyr, 526Asn, 526Leu, 533Pro, and 572Phe) made up 13.1% and 10.6% of all mutations in strains from Bangladesh and Kinshasa, respectively. Except for the 511Pro and 526Asn mutations, most of these strains with disputed mutations tested rifampin resistant in routine Löwenstein-Jensen medium proportion method drug susceptibility testing (DST; 78.7%), but significantly less than those with common, undisputed mutations (96.3%). With 63% of patients experiencing failure or relapse in both groups, there was no difference in outcome of first-line retreatment between patients carrying a strain with disputed versus common mutations. We conclude that rifampin resistance that is difficult to detect by the gold standard, phenotypic DST, is clinically and epidemiologically highly relevant. Sensitivity rather than specificity is imperfect with any rifampin DST method. Even at a low prevalence of rifampin resistance, a rifampin-resistant result issued by a competent laboratory may not warrant confirmation, although the absence of a necessity for confirmation needs to be confirmed for molecular results among new cases. However, a result of rifampin susceptibility should be questioned when suspicion is very high, and further DST using a different system (i.e., genotypic after phenotypic testing) would be fully justified.
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