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.

Incidence of tuberculosis is high in chronic kidney disease patients in South East England and drug resistance common.

The risk of tuberculosis (TB) is significantly increased in chronic kidney disease (CKD). Data on TB in CKD in the UK are sparse; most information stems from countries with high background prevalence. The aim of this study was to estimate the incidence of TB in CKD patients in South East London and to describe the epidemiology, treatment, and outcome. CKD patients with TB between 1994 and 2010 were identified retrospectively. Data were collected on type of renal replacement therapy, the method of TB diagnosis, disease site, treatment regimens, and risk factors. Forty patients were identified of whom 67.5% had CKD stages IV-V. Sixty-five percent were from non-UK born ethnic minorities. Median time from diagnosis of CKD to TB development was 12 months (range 0-192 months). Cumulative incidence of TB was 1267/100,000 [95% confidence interval (CI): 630-1904; 85 × background UK rate] in hemodialysis patients; 398/100,000 (95% CI: 80-1160; 26 × background UK rate) in peritoneal dialysis; and 522/100,000 (CI: 137-909; 35 × background UK rate) in transplant recipients. Sixty-three percent of patients had pulmonary TB and 25% of patients with culture-positive TB had resistant isolates. Fifty percent of patients were immunosuppressed due to drugs, diabetes, and/or retroviral disease. Treatment regimens were according to recent national guidance in 73% of cases. Seventy-six percent of patients experienced side effects. Greater awareness of risk factors, drug resistance, treatment regimens, and potential side effects is needed.

Ethnic variation in inflammatory profile in tuberculosis.

Distinct phylogenetic lineages of Mycobacterium tuberculosis (MTB) cause disease in patients of particular genetic ancestry, and elicit different patterns of cytokine and chemokine secretion when cultured with human macrophages in vitro. Circulating and antigen-stimulated concentrations of these inflammatory mediators might therefore be expected to vary significantly between tuberculosis patients of different ethnic origin. Studies to characterise such variation, and to determine whether it relates to host or bacillary factors, have not been conducted. We therefore compared circulating and antigen-stimulated concentrations of 43 inflammatory mediators and 14 haematological parameters (inflammatory profile) in 45 pulmonary tuberculosis patients of African ancestry vs. 83 patients of Eurasian ancestry in London, UK, and investigated the influence of bacillary and host genotype on these profiles. Despite having similar demographic and clinical characteristics, patients of differing ancestry exhibited distinct inflammatory profiles at presentation: those of African ancestry had lower neutrophil counts, lower serum concentrations of CCL2, CCL11 and vitamin D binding protein (DBP) but higher serum CCL5 concentrations and higher antigen-stimulated IL-1 receptor antagonist and IL-12 secretion. These differences associated with ethnic variation in host DBP genotype, but not with ethnic variation in MTB strain. Ethnic differences in inflammatory profile became more marked following initiation of antimicrobial therapy, and immunological correlates of speed of elimination of MTB from the sputum differed between patients of African vs. Eurasian ancestry. Our study demonstrates a hitherto unappreciated degree of ethnic heterogeneity in inflammatory profile in tuberculosis patients that associates primarily with ethnic variation in host, rather than bacillary, genotype. Candidate immunodiagnostics and immunological biomarkers of response to antimicrobial therapy should be derived and validated in tuberculosis patients of different ethnic origin.

Vitamin D accelerates resolution of inflammatory responses during tuberculosis treatment.

Calcidiol, the major circulating metabolite of vitamin D, supports induction of pleiotropic antimicrobial responses in vitro. Vitamin D supplementation elevates circulating calcidiol concentrations, and thus has a potential role in the prevention and treatment of infection. The immunomodulatory effects of administering vitamin D to humans with an infectious disease have not previously been reported. To characterize these effects, we conducted a detailed longitudinal study of circulating and antigen-stimulated immune responses in ninety-five patients receiving antimicrobial therapy for pulmonary tuberculosis who were randomized to receive adjunctive high-dose vitamin D or placebo in a clinical trial, and who fulfilled criteria for per-protocol analysis. Vitamin D supplementation accelerated sputum smear conversion and enhanced treatment-induced resolution of lymphopaenia, monocytosis, hypercytokinaemia, and hyperchemokinaemia. Administration of vitamin D also suppressed antigen-stimulated proinflammatory cytokine responses, but attenuated the suppressive effect of antimicrobial therapy on antigen-stimulated secretion of IL-4, CC chemokine ligand 5, and IFN-α. We demonstrate a previously unappreciated role for vitamin D supplementation in accelerating resolution of inflammatory responses during tuberculosis treatment. Our findings suggest a potential role for adjunctive vitamin D supplementation in the treatment of pulmonary infections to accelerate resolution of inflammatory responses associated with increased risk of mortality.

The geographic diversity of nontuberculous mycobacteria isolated from pulmonary samples: an NTM-NET collaborative study.

A significant knowledge gap exists concerning the geographical distribution of nontuberculous mycobacteria (NTM) isolation worldwide. To provide a snapshot of NTM species distribution, global partners in the NTM-Network European Trials Group (NET) framework (www.ntm-net.org), a branch of the Tuberculosis Network European Trials Group (TB-NET), provided identification results of the total number of patients in 2008 in whom NTM were isolated from pulmonary samples. From these data, we visualised the relative distribution of the different NTM found per continent and per country. We received species identification data for 20 182 patients, from 62 laboratories in 30 countries across six continents. 91 different NTM species were isolated. Mycobacterium avium complex (MAC) bacteria predominated in most countries, followed by M. gordonae and M. xenopi. Important differences in geographical distribution of MAC species as well as M. xenopi, M. kansasii and rapid-growing mycobacteria were observed. This snapshot demonstrates that the species distribution among NTM isolates from pulmonary specimens in the year 2008 differed by continent and differed by country within these continents. These differences in species distribution may partly determine the frequency and manifestations of pulmonary NTM disease in each geographical location.

High-dose vitamin D(3) during intensive-phase antimicrobial treatment of pulmonary tuberculosis: a double-blind randomised controlled trial.

BACKGROUND: Vitamin D was used to treat tuberculosis in the pre-antibiotic era, and its metabolites induce antimycobacterial immunity in vitro. Clinical trials investigating the effect of adjunctive vitamin D on sputum culture conversion are absent. METHODS: We undertook a multicentre randomised controlled trial of adjunctive vitamin D in adults with sputum smear-positive pulmonary tuberculosis in London, UK. 146 patients were allocated to receive 2·5 mg vitamin D(3) or placebo at baseline and 14, 28, and 42 days after starting standard tuberculosis treatment. The primary endpoint was time from initiation of antimicrobial treatment to sputum culture conversion. Patients were genotyped for TaqI and FokI polymorphisms of the vitamin D receptor, and interaction analyses were done to assess the influence of the vitamin D receptor genotype on response to vitamin D(3). This trial is registered with ClinicalTrials.gov number NCT00419068. FINDINGS: 126 patients were included in the primary efficacy analysis (62 assigned to intervention, 64 assigned to placebo). Median time to sputum culture conversion was 36·0 days in the intervention group and 43·5 days in the placebo group (adjusted hazard ratio 1·39, 95% CI 0·90-2·16; p=0.14). TaqI genotype modified the effect of vitamin D supplementation on time to sputum culture conversion (p(interaction)=0·03), with enhanced response seen only in patients with the tt genotype (8·09, 95% CI 1·36-48·01; p=0·02). FokI genotype did not modify the effect of vitamin D supplementation (p(interaction)=0·85). Mean serum 25-hydroxyvitamin D concentration at 56 days was 101·4 nmol/L in the intervention group and 22·8 nmol/L in the placebo group (95% CI for difference 68·6-88·2; p<0·0001). INTERPRETATION: Administration of four doses of 2·5 mg vitamin D(3) increased serum 25-hydroxyvitamin D concentrations in patients receiving intensive-phase treatment for pulmonary tuberculosis. Vitamin D did not significantly affect time to sputum culture conversion in the whole study population, but it did significantly hasten sputum culture conversion in participants with the tt genotype of the TaqI vitamin D receptor polymorphism. FUNDING: British Lung Foundation.

Non-tuberculous slow-growing mycobacterial pulmonary infections in non-HIV-infected patients in south London.

BACKGROUND: UK data on slow-growing non-tuberculous mycobacterial (NTM) pulmonary infections are sparse and there is little consensus on optimal treatment regimens. METHODS: This was a retrospective study of NTM pulmonary infections in a London teaching hospital. Inclusion criteria were culture of slow-growing mycobacteria between 2000 and 2007, age > 18 y, HIV-negative, and meeting American Thoracic Society criteria. RESULTS: Fifty-seven patients were included; 68% were males and the median age was 61 y. Predisposing factors were smoking (70%), alcohol abuse (28%), and chronic obstructive pulmonary disease (37%). Cavitation (56%) and infiltrates (42%) were common radiological findings. The predominant organism was Mycobacterium kansasii (70%). Ninety-three percent of patients with M. kansasii, 63% with Mycobacterium avium intracellulare, 60% with Mycobacterium malmoense, and 25% with Mycobacterium xenopi had clinical disease. Of the 57 patients, 37 were treated and had follow-up data available. Most patients received 3 drugs: rifampicin, ethambutol, and clarithromycin or ciprofloxacin for at least 9 months. Thirty percent experienced drug side effects. M. kansasii treatment had a 100% cure and 10% relapse rate, but 15% died. CONCLUSIONS: M. kansasii was the most common NTM and its isolation was predictive of clinical disease. Compared with other studies, treatment with 3 agents had a similar rate of cure and did not appear to reduce the relapse rate of disease, but did increase the risk of side effects.

Non tuberculous mycobacteria pulmonary disease: patients and clinicians working together to improve the evidence base for care.

Non-tuberculous mycobacterial pulmonary disease is on the rise globally. It is often missed, and causes significant morbidity and even mortality. Here, members of a clinical research network and a patient support group discuss some of the current key issues in NTM management. In addition to the need for research into epidemiology, immunology and treatment, we recommend greater use of patient and clinician networks to: (i) educate primary and secondary care clinicians to develop a high index of suspicion when investigating and treating at risk populations. (ii) promote a multidisciplinary team. (iii) promote shared patient-clinician decision making throughout care. (iv) incorporate use of patient self-report measures to assess progress and outcomes. (v) increase education of patients on their illness and its management. (vi) recruit patients into research projects and registries to improve the clinical evidence base. (vii) increase co-production of research with key stakeholders such as patients and their families, using expert patients and patient groups. (viii) understand more about the psychological, social and economic consequences of the disease.

British Thoracic Society Guideline for the management of non-tuberculous mycobacterial pulmonary disease (NTM-PD).

The full guideline for the management of non-tuberculous mycobacterial pulmonary disease is published in Thorax. The following is a summary of the recommendations and good practice points. The sections referred to in the summary refer to the full guideline.

How should we treat tuberculosis in adult patients with chronic kidney disease? Key messages from the British Thoracic Society Guidelines.

This review highlights the key messages from the 2010 British Thoracic Society Guidelines on the management of Mycobacterium tuberculosis infection and disease in adult patients with chronic kidney disease. These guidelines were developed in response to many requests for advice from respiratory and infectious diseases physicians who treat patients with tuberculosis, as there was very little information available to help clinicians manage the disease in this population of often very sick patients. Renal units in the United Kingdom were prescribing variable chemoprophylaxis regimens that frequently had no basis in evidence, and drug doses used to treat tuberculosis were often inappropriate because of clinicians' natural concern about poisoning a patient with little or no renal function. The guidelines address these issues together with when and how to screen for latent infection and the different needs of patients with renal impairment, those needing dialysis and those with a transplanted kidney. It became very clear in compiling these guidelines that there is a shortage of both background information on rates of tuberculosis in such patients in countries with low background prevalence, and good randomized controlled trials of treatment regimens. Wherever possible, the recommendations made are evidence-based, but this was not always available. This review gives a summary of those recommendations and reiterates some of the important messages; in particular, tuberculosis should be managed with the full involvement of the chest or infectious diseases physician who is the local lead for this important infection.