Fluoroquinolones and isoniazid-resistant tuberculosis: implications for the 2018 WHO guidance.

INTRODUCTION: 2018 World Health Organization (WHO) guidelines for the treatment of isoniazid (H)-resistant (Hr) tuberculosis recommend a four-drug regimen: rifampicin (R), ethambutol (E), pyrazinamide (Z) and levofloxacin (Lfx), with or without H ([H]RZE-Lfx). This is used once Hr is known, such that patients complete 6 months of Lfx (≥6[H]RZE-6Lfx). This cohort study assessed the impact of fluoroquinolones (Fq) on treatment effectiveness, accounting for Hr mutations and degree of phenotypic resistance. METHODS: This was a retrospective cohort study of 626 Hr tuberculosis patients notified in London, 2009-2013. Regimens were described and logistic regression undertaken of the association between regimen and negative regimen-specific outcomes (broadly, death due to tuberculosis, treatment failure or disease recurrence). RESULTS: Of 594 individuals with regimen information, 330 (55.6%) were treated with (H)RfZE (Rf=rifamycins) and 211 (35.5%) with (H)RfZE-Fq. The median overall treatment period was 11.9 months and median Z duration 2.1 months. In a univariable logistic regression model comparing (H)RfZE with and without Fqs, there was no difference in the odds of a negative regimen-specific outcome (baseline (H)RfZE, cluster-specific odds ratio 1.05 (95% CI 0.60-1.82), p=0.87; cluster NHS trust). Results varied minimally in a multivariable model. This odds ratio dropped (0.57, 95% CI 0.14-2.28) when Hr genotype was included, but this analysis lacked power (p=0.42). CONCLUSIONS: In a high-income setting, we found a 12-month (H)RfZE regimen with a short Z duration to be similarly effective for Hr tuberculosis with or without a Fq. This regimen may result in fewer adverse events than the WHO recommendations

Fluoroquinolones and isoniazid resistant TB: implications for the 2018 WHO guidance

Introduction: 2018 World Health Organization (WHO) guidelines for the treatment of isoniazid (H)-resistant (Hr) tuberculosis recommend a four-drug regimen: rifampicin (R), ethambutol (E), pyrazinamide (Z) and levofloxacin (Lfx), with or without H ([H]RZE-Lfx). This is used once Hr is known, such that patients complete 6 months of Lfx (≥6[H]RZE-6Lfx). This cohort study assessed the impact of fluoroquinolones (Fq) on treatment effectiveness, accounting for Hr mutations and degree of phenotypic resistance. / Methods: This was a retrospective cohort study of 626 Hr tuberculosis patients notified in London, 2009–2013. Regimens were described and logistic regression undertaken of the association between regimen and negative regimen-specific outcomes (broadly, death due to tuberculosis, treatment failure or disease recurrence). / Results: Of 594 individuals with regimen information, 330 (55.6%) were treated with (H)RfZE (Rf=rifamycins) and 211 (35.5%) with (H)RfZE-Fq. The median overall treatment period was 11.9 months and median Z duration 2.1 months. In a univariable logistic regression model comparing (H)RfZE with and without Fqs, there was no difference in the odds of a negative regimen-specific outcome (baseline (H)RfZE, cluster-specific odds ratio 1.05 (95% CI 0.60–1.82), p=0.87; cluster NHS trust). Results varied minimally in a multivariable model. This odds ratio dropped (0.57, 95% CI 0.14–2.28) when Hr genotype was included, but this analysis lacked power (p=0.42). / Conclusions: In a high-income setting, we found a 12-month (H)RfZE regimen with a short Z duration to be similarly effective for Hr tuberculosis with or without a Fq. This regimen may result in fewer adverse events than the WHO recommendations

Thionine Interaction to DNA: Comparative Spectroscopic Studies on Double Stranded Versus Single Stranded DNA

Interaction of thionine with double stranded and single stranded calf thymus DNA has been studied by absorbance, fluorescence, competition dialysis, circular dichroism and isothermal titration calorimetry. Binding to the native double stranded DNA conformation induced strong quenching in fluorescence spectrum of thionine. Linear Scatchard plots indicated the binding to be of one type and the affinity values evaluated to be of the order of 105 M−1 with double stranded DNA. Fluorescence quenching was much weaker with single stranded DNA and the binding affinity was about one order lower. Ferrocyanide quenching studies revealed that the fluorescence emission of dye molecules bound to the double stranded DNA was quenched much less compared to those bound to the single stranded DNA. Furthermore, there was significant emission polarization for the bound dye molecules and strong energy transfer from the DNA base pairs to the dye molecules indicating intercalative binding to ds DNA. Salt dependence of the binding phenomenon revealed that electrostatic forces played a significant role in the binding process. The intercalation of the dye molecules to double stranded DNA and simple stacking to single strands was proved from these fluorescence techniques. Support to the fluorescence results have been derived from absorption, circular dichroic and dialysis results. Calorimetric studies suggested that the binding to ds DNA conformation was both enthalpy and entropy favoured while that to ss DNA was predominantly entropy favoured