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 the genome that confer phenotypic drug resistance. However, there have been few data published regarding the relationships between the detected resistance 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 between resistance mutations and patient mortality. The presence of an 1401G 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. Specific and resistance mutations, associated with high-level resistance, were associated with patient mortality as identified in clinical isolates 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.).

Molecular Targets Related Drug Resistance Mechanisms in MDR-, XDR-, and TDR-Mycobacterium tuberculosis Strains

“…Unfortunately, development of drug resistance in the form of monoresistant-TB or MDR-/XDR-/TDR-TB critically obstructs the efficacy of currently available drug regimens. Improper use of antibiotics, lack of treatment adherence, mutational modifications, and limited access to drugs or diagnostic tools all are risk factors associated with the emergence of resistant forms of TB (Lange et al, 2014 ; Georghiou et al, 2017 ; Manson et al, 2017 ). Besides, acquired drug-resistant TB and transmitted drug-resistant TB pose a serious threat to global TB control and population health.…”

Drug resistance gene mutations and treatment outcomes in MDR-TB: A prospective study in Eastern China

“…In contrast, the moderate-level resistance mediated by gyrA gene mutation did not show a significant statistical effect [ 34 ]. A multinational cohort study also suggested the role of high-level resistance-related gyrA mutations increased the risk of death for MDR/XDR-TB patients [ 35 ]. High doses of Mfx added to the MDR-TB treatment regimen can prevent patients from developing XDR-TB, indicating that low concentrations of FQ resistance caused by mutations in the gyrA locus can be treated with high doses of Mfx [ 36 ].…”

Multidrug Resistance (MDR) and Collateral Sensitivity in Bacteria, with Special Attention to Genetic and Evolutionary Aspects and to the Perspectives of Antimicrobial Peptides—A Review

“…The resistance genotype [ 49 , 50 , 51 ] determines the resistance phenotype. Take the evolutionary history of Mycobacterium tuberculosis resistance to second-line anti-tuberculous as a scholarly medical genetic example to illustrate the simple Mendelian genotype–phenotype relations [ 52 , 53 , 54 , 55 ].…”

“…The higher level of organization is the antibiotics resistance cassette [ 62 , 63 , 64 ]. The respective resistance gene(s) could be localized either on the chromosome [ 51 ], or in a plasmid [ 65 , 66 , 67 , 68 , 69 ], either as non-conjugative [ 62 ], conjugative [ 70 , 71 ], or in an episome [ 72 ].…”