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.

The Changing Landscape of Childhood Tuberculosis in the United Kingdom: A Retrospective Cohort (2000-2015).

BACKGROUND: The epidemiology of tuberculosis (TB) is changing in the United Kingdom and globally. Childhood TB is a key indicator of recent transmission and provides a marker of wider TB control. We describe the recent epidemiology of childhood TB in the United Kingdom, how this compares to TB in adults, and document changes with time. METHODS: TB cases notified in the United Kingdom between 2000 and 2015 were categorized as children (<15 years of age) or adults (≥15 years of age). Descriptive analyses were carried out on demographic, clinical and microbiologic data. We carried out logistic regressions to identify risk factors associated with children having no microbiologic confirmation. RESULTS: In the study period, 6293 TB cases (5%) in the United Kingdom were notified in children. Childhood TB incidence declined from 487 cases in 2000 (3.4 per 100,000) to 232 cases (2.0 per 100,000) in 2015. The majority (68%) of children with TB were UK born, with a high proportion of Pakistani (24%) and Black-African (22%) ethnicity. Sixty-four percent of children had pulmonary disease. Culture confirmation was low (24%). Children who were younger, UK born and those with extrapulmonary disease were less likely to have microbiologically confirmed TB. A high proportion (87%) of children completed treatment at last-recorded outcome, with few deaths (39 cases; 0.7%). CONCLUSIONS: The incidence of TB in children in the United Kingdom has decreased in the past 16 years, with the majority of children completing TB treatment. Ongoing monitoring of childhood TB will provide a measure of the effectiveness of the national TB program.

Towards better guidance on caseload thresholds to promote positive tuberculosis treatment outcomes: a cohort study.

BACKGROUND: In low-incidence countries, clinical experience of tuberculosis is becoming more limited, with potential consequences for patient outcomes. In 2007, the Department of Health released a guidance 'toolkit' recommending that tuberculosis patients in England should not be solely managed by clinicians who see fewer than 10 cases per year. This caseload threshold was established to try to improve treatment outcomes and reduce transmission, but was not evidence based. We aimed to assess the association between clinician or hospital caseload and treatment outcomes, as well as the relative suitability of making recommendations using each caseload parameter. METHODS: Demographic and clinical data for tuberculosis cases in England notified to Public Health England's Enhanced Tuberculosis Surveillance system between 2003 and 2012 were extracted. Mean clinician and hospital caseload over the past 3 years were calculated and treatment outcomes grouped into good/neutral and unfavourable. Caseloads over time and their relationship with outcomes were described and analysed using random effects logistic regression, adjusted for clustering. RESULTS: In a fully adjusted multivariable model (34,707 cases)there was very strong evidence that management of tuberculosis by clinicians with fewer than 10 cases per year was associated with greater odds of an unfavourable outcome compared to clinicians who managed greater numbers of cases (cluster-specific odds ratio, 1.14; 95 % confidence interval, 1.05-1.25; P = 0.002). The relationship between hospital caseload and treatment outcomes was more complex and modified by a patient's place of birth and ethnicity. The clinician caseload association held after adjustment for hospital caseload and when the clinician caseload threshold was reduced down to one. CONCLUSIONS: Despite the relative ease of making recommendations at the hospital level and the greater reliability of recorded hospital versus named clinician, our results suggest that clinician caseload thresholds are more suitable for clinical guidance. The current recommended clinician caseload threshold is functional. Sensitivity analyses reducing the threshold indicated that clinical experience is pertinent even at very low average caseloads, which is encouraging for low burden settings.