Treatment of MDR tuberculosis involves substantial risk of acquired resistance to SLDs, increasing as baseline drug resistance increases. The risk was significantly lower in programs documented by the GLC to meet specific standards.

Definitive clinical trials of new chemotherapies for tuberculosis (TB) treatment require following subjects until at least six months after treatment discontinuation to assess for durable cure, making these trials expensive and lengthy. Surrogate endpoints relating to treatment failure and relapse are currently limited to sputum microbiology, which has limited sensitivity and specificity. In this study we prospectively assessed radiographic changes using 2-deoxy-2-[18F]-fluoro-D-glucose (FDG) positron emission tomography/computed tomography (PET/CT) at two months and six months (CT only) in a cohort of subjects with multidrug-resistant (MDR) TB who were treated with second-line TB therapy for two years and then followed for an additional six months. CT scans were read semi-quantitatively by radiologists and computationally evaluated using custom software to provide volumetric assessment of TB-associated abnormalities. CT scans at six months assessed by readers were predictive of outcomes but not two months and changes in computed abnormal volumes were predictive at both time points. Quantitative changes in FDG uptake two months after starting treatment were associated with long-term outcomes. In this cohort, some radiologic markers were more sensitive than conventional sputum microbiology in distinguishing successful from unsuccessful treatment. These results support the potential of imaging biomarkers as possible surrogate endpoints in clinical trials of new TB drug regimens. Larger cohorts confirming these results are needed.

Increasing drug resistance was associated in a logical stepwise manner with poor treatment outcomes. Acquired resistance was worse than initial resistance to the same drugs. Increasing numbers of effective drugs, specific drugs, and specific program characteristics were associated with better outcomes and less acquired resistance.

The aminoglycosides streptomycin, amikacin, and kanamycin and the cyclic polypeptide capreomycin are all widely used in second-line therapy for patients who develop multidrug-resistant tuberculosis. We have characterized a set of 106 clinical isolates of Mycobacterium tuberculosis using phenotypic drug susceptibility testing (DST) to determine the extent of resistance to each agent and cross-resistance between agents. These results were compared with polymorphisms in the DNA sequences of ribosome-associated genes previously implicated in resistance and with the clinical outcomes of subjects from whom these isolates were obtained. Thirty-six (34%) of these isolates displayed resistance to one or more of these agents, and the majority of these (20 of 36) showed cross-resistance to one or more agents. Most (33 of 36) of the resistant isolates showed polymorphisms in the 16S ribosome components RpsL and rrs. Three resistant strains (3 of 36) were identified that had no known polymorphisms in ribosomal constituents. For kanamycin and streptomycin, molecular DST significantly outperformed phenotypic DST using the absolute concentration method for predicting 4-month sputum conversion (likelihood ratios of 4.0 and 2.0, respectively) and was equivalent to phenotypic DST using the National Committee for Clinical Laboratory Standards (NCCLS)-approved agar proportion method for estimating MIC (likelihood ratio, 4.0). These results offer insight into mechanisms of resistance and crossresistance among these agents and suggest that the development of rapid molecular tests to distinguish polymorphisms would significantly enhance clinical utility of this important class of second-line antituberculosis drugs.Drug-resistant tuberculosis (TB) is an emerging issue in global TB control, with multidrug-resistant (MDR) and extensively drug-resistant (XDR) disease threatening to overwhelm existing initiatives (8). The difference between MDR TB (resistant to at least isoniazid [INH] and rifampin [RIF]) and XDR TB (MDR plus resistant to any fluoroquinolone and at least one of the injectable second-line drugs amikacin [AK], kanamycin [KM], and capreomycin [CM]) is often life or death for patients suffering from drug-resistant TB (7,14,15). Nonetheless, the diagnosis of MDR and XDR TB remains a lengthy, technically demanding laboratory procedure relying on culturing bacteria isolated from patient sputum on solid or liquid medium in the presence of individual drugs. To make matters worse, such highly resistant strains occasionally show growth differences in in vitro culture that may be related to fitness costs imposed by the mutations conferring resistance (9). These growth differences, and the complexity of in vitro assessment of drug resistance, result in laboratory determinations of XDR of questionable reliability (16). There is a growing movement toward molecular drug susceptibility testing using a variety of detection platforms that show robust performance for the firstline agents that define MDR TB (10).Molecular drug susceptibility t...

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