title: Increased Tuberculosis Patient Mortality Associated with Mycobacterium tuberculosis Mutations Conferring Resistance to Second-Line Antituberculous Drugs.
abstract: Rapid molecular diagnostics have great potential to limit the spread of multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) (M/XDR-TB). These technologies detect mutations in theMycobacterium tuberculosisgenome that confer phenotypic drug resistance. However, there have been few data published regarding the relationships between the detectedM. tuberculosisresistance mutations and M/XDR-TB treatment outcomes, limiting our current ability to exploit the full potential of molecular diagnostics. We analyzed clinical, microbiological, and sequencing data for 451 patients and their clinical isolates collected in a multinational, observational cohort study to determine if there was an association betweenM. tuberculosisresistance mutations and patient mortality. The presence of anrrs1401G mutation was associated with significantly higher odds of patient mortality (adjusted odds ratio [OR] = 5.72; 95% confidence interval [CI], 1.65 to 19.84]) after adjusting for relevant patient clinical characteristics and all other resistance mutations. Further analysis of mutations, categorized by the associated resistance level, indicated that the detection of mutations associated with high-level fluoroquinolone (OR, 3.99 [95% CI, 1.10 to 14.40]) and kanamycin (OR, 5.47 [95% CI, 1.64 to 18.24]) resistance was also significantly associated with higher odds of patient mortality, even after accounting for clinical site, patient age, reported smoking history, body mass index (BMI), diabetes, HIV, and all other resistance mutations. SpecificgyrAandrrsresistance mutations, associated with high-level resistance, were associated with patient mortality as identified in clinicalM. tuberculosisisolates from a diverse M/XDR-TB patient population at three high-burden clinical sites. These results have important implications for the interpretation of molecular diagnostics, including identifying patients at increased risk for mortality during treatment. (This study has been registered at ClinicalTrials.gov under registration no. NCT02170441.).
authors.affiliation: Foundation for Innovative New Diagnostics, Geneva, Switzerland sophia.georghiou@finddx.org.
authors.forename: Sophia B
authors.initials: SB
authors.lastname: Georghiou
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, California, USA.
authors.forename: Marva
authors.initials: M
authors.lastname: Seifert
authors.affiliation: University of Arkansas, Fayetteville, Arkansas, USA.
authors.forename: Donald G
authors.identifier: 0000-0003-1760-0574
authors.initials: DG
authors.lastname: Catanzaro
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, California, USA.
authors.forename: Richard S
authors.initials: RS
authors.lastname: Garfein
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, California, USA.
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Rodwell
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000995:Antitubercular Agents / Q000494:pharmacology*; D001431:Bacteriological Techniques; D002648:Child; D015331:Cohort Studies; D024881:Drug Resistance, Bacterial; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000235:genetics* / Q000302:isolation & purification; D018570:Risk Assessment; D017422:Sequence Analysis, DNA; D016019:Survival Analysis; D018088:Tuberculosis, Multidrug-Resistant / Q000382:microbiology / Q000401:mortality*; D055815:Young Adult
chemical_list: D000995:Antitubercular Agents
keywords: Mycobacterium tuberculosis; diagnostics; molecular genetics; multidrug resistance