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, 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% confidence interval 0.60–1.82], p-value 0.87; cluster NHS Trust). Results varied minimally in a multivariable model. This odds ratio dropped (0.57 [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 TB with or without a Fq. This regimen may result in fewer adverse events than the WHO recommendations.