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Treatment for multidrug-resistant tuberculosis (MDR TB) is associated with adverse events (AE). Patients treated with an MDR TB regimen in Hospital Nossa Senhora da Paz, Cubal, Angola, were prospectively enrolled from May 2013 to July 2015. Baseline characteristics, AE, and clinical and microbiological outcomes were recorded. A total of 216 patients were treated with an MDR TB regimen and 179 (82.9%) patients developed at least one AE. The most common AE were elevation of liver enzymes (46.8% of patients), elevated creatinine (44.4% of patients), and ototoxicity (40.7% of patients). Previous TB treatment was associated with the occurrence of AE (OR 4.89, 95% CI: 2.09-11.46, P < 0.001) and months on treatment was associated to severe AE (OR 1.11 95% CI: 1.04-1.18, P = 0.001). Successful treatment was achieved in 117 (54.2%) patients. Incidence of AE was associated with an unsuccessful outcome (OR 1.23, 95% CI: 1.09-1.40, P = 0.001). Patients treated with MDR TB treatment frequently experience AE, and these are related with previous TB treatment and duration of treatment. Given the high percentage of patients experiencing AE and the low treatment success rates, more effective and less toxic drugs to treat MDR TB are urgently needed.

Multidrug resistance has become a problem in the management of tuberculosis, leading to an urgent need for research related to new regimens including the currently available drugs. The objectives of this study were: (i) to study the effect of the following second-choice three-drug combinations against multidrug-resistant (MDR) and drug-susceptible clinical isolates (levofloxacin, linezolid and ethambutol; levofloxacin, amikacin and ethambutol; and levofloxacin, linezolid and amikacin); and (ii) to compare the effect of these combinations with an isoniazid, rifampicin and ethambutol combination against drug-susceptible clinical isolates. A total of 9 MDR clinical and 12 drug-susceptible isolates (11 clinical isolates and the H37Rv reference strain) were studied using an adaptation of the chequerboard assay. The fractional inhibitory concentration index (FICI) was calculated as follows: FICI=FIC(A)+FIC(B)+FIC(C)=A/MIC(A)+B/MIC(B)+C/MIC(C), where A, B and C are the minimum inhibitory concentrations (MICs) of each antibiotic in combination and MIC(A), MIC(B) and MIC(C) are the individual MICs. The FICI was interpreted as synergism when the value was <0.75. The FICI of all the combinations ranged from 1.5 to 3, showing indifferent activity. No differences were found between MDR and drug-susceptible isolates, or between the second-choice combinations and the fourth combination against drug-susceptible isolates. In conclusion, the second-choice drugs are equally effective as the combination of isoniazid, rifampicin and ethambutol., (Copyright © 2013 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.)

The aim of this study was to evaluate the reliability of the VersaTREK system for Mycobacterium tuberculosis drug susceptibility testing compared with results obtained with the Bactec MGIT 960 system. A total of 67 strains were evaluated. Overall agreement was at 98.5%. Kappa indexes were 1.0 for isoniazid, rifampin, and ethambutol, 0.937 for pyrazinamide, and 0.907 for streptomycin. The VersaTREK system is validated for M. tuberculosis drug susceptibility testing.

We studied the presence of mutations in the whole katG gene and specific regions of the oxyR-ahpC and mabA-inhA regulatory region in 61 Mycobacterium tuberculosis isoniazid-resistant isolates. An 81-bp region of the rpoB gene was also sequenced in 17 rifampin-resistant strains. Alterations in the katG gene were detected in 55% of the isolates. Mutation in codon 315 was the most prevalent (32%). Strains showed a high level of resistance, and most maintained a substantial catalase-peroxidase activity. Three strains with an isoniazid MIC of >or=32 microg/ml lacked catalase-peroxidase activity. Two of them had deletions in the catalytic domain of the KatG protein. One strain with deletion and three strains with mutations in the C-terminal domain showed low-level resistance and conserved the catalase-peroxidase activity. Mutations in the mabA-inhA regulatory region were identified in 32% of the isolates. All had low-level resistance, and the vast majority conserved catalase-peroxidase activity. Seventeen percent of the isoniazid-resistant isolates had no detectable alterations at the studied loci. Resistance to rifampin was associated with mutations in the 81-bp of the rpoB gene in all cases. IS6110 analysis indicated that recent transmission contributed substantially to the emergence of isoniazid- resistant tuberculosis in Barcelona through short transmission chains. A rapid genotypic assay, including the 315-katG codon and the -15 nucleotide of the mabA-inhA regulatory region, may cover 62% of isoniazid- resistant strains in Barcelona. In contrast, the targeting of the 81-bp region of rpoB would detect all our rifampin-resistant isolates.

Background: This study evaluates a method based on real-time PCR for direct detection in clinical samples of the common mutations responsible for isoniazid and rifampicin resistance of Mycobacterium tuberculosis., Methods: Six pairs of fluorogenic 5' exonuclease probes (Taqman), mutated and wild-type, were designed for six targets: codon 315 of katG, substitution C209T in the regulatory region of inhA, and codons 513, 516, 526 and 531 of rpoB., Results: A total of 98 clinical samples harbouring resistant bacilli from 55 patients and 126 samples harbouring susceptible bacilli from 126 patients were processed. The isolates from samples were tested for drug susceptibility with the radiometric method and sequenced for the same genetic targets. Among the samples, 93 harboured isoniazid-resistant bacilli. According to the sequencing results, 30 had mutations in katG, 30 in inhA and 33 (35.4%) had no mutations in these targets. All 27 clinical specimens harbouring rifampicin-resistant bacilli showed mutations in rpoB. The detection threshold of this method in detecting target genes in serial dilutions of artificial samples was 1.5 x 10(3) cfu/mL. In clinical samples, the sensitivity ranged from 30.4 to 35.3% for smear-negative samples and from 95.1 to 99.2% for smear-positive samples, with a specificity of 100%. In this study, the overall sensitivity in detecting patients having the target mutations was 74.3%., Conclusions: The main advantage of the described method is the possibility of detecting rifampicin and isoniazid resistance within 48-72 h after sample collection, with a sensitivity of nearly 100% in smear-positive samples if the chosen target is responsible for the resistance.

Setting: Five districts in Equatorial Guinea, March 1999 to February 2001., Objectives: To determine tuberculosis drug resistance among new and previously treated cases, the risk factors associated with resistance, and the mutations associated with isoniazid and rifampicin (katG, inhA and rpoB genes) resistance, and to genotype resistant strains., Results: A positive culture identified as Mycobacterium tuberculosis complex was obtained in 240/499 patients. Susceptibility testing was performed in 236 strains. The overall resistance rate in new cases was 16.9% compared to 41.6% in previously treated cases. Isoniazid resistance was the most frequent (respectively 12.5% and 16.6%) in the two groups, while multidrug resistance was observed in 1.7% and 25% of new and previously treated cases, respectively. Female sex was statistically associated with resistance in new cases. Of 41 isoniazid-resistant strains, 33 (80.5%) had mutations in the inhA gene; none had mutations in the katG gene and eight had no mutations in either gene. All strains had low-level isoniazid resistance. Of eight strains resistant to rifampicin, six had mutations in the rpoB gene. Genotyping defined seven clusters., Conclusions: Moderate resistance was found in new cases. Low-level isoniazid resistance predominated among mutations in the inhA gene, with a high percentage of clustering in resistant strains.