Treatment Regimens For Drug-resistant Tuberculosis Research Articles

Towards shorter, safer, flexible, and more effective treatment regimens for drug-resistant tuberculosis

Towards shorter, safer, flexible, and more effective treatment regimens for drug-resistant tuberculosis

Pharmacokinetics of anti-TB drugs in children and adolescents with drug-resistant TB: a multicentre observational study from India.

Drug-resistant tuberculosis (DR-TB) is one of the challenging forms of TB to treat, not only in adults but also in children and adolescents. Further, there is a void in the treatment strategy exclusively for children due to various reasons, including paucity of pharmacokinetic (PK) data on anti-TB drugs across the globe. In this context, the present study aimed at assessing the PK of some of the anti-TB drugs used in DR-TB treatment regimens. A multicentre observational study was conducted among DR-TB children and adolescents (n = 200) aged 1-18 years (median: 12 years; IQR: 9-14) treated under programmatic settings in India. Steady-state PK (intensive: n = 89; and sparse: n = 111) evaluation of moxifloxacin, levofloxacin, cycloserine, ethionamide, rifampicin, isoniazid and pyrazinamide was carried out by measuring plasma levels using HPLC methods. In the study population, the frequency of achieving peak plasma concentrations ranged between 13% (for rifampicin) to 82% (for pyrazinamide), whereas the frequency of suboptimal peak concentration for pyrazinamide, cycloserine, moxifloxacin, levofloxacin and rifampicin was 15%, 19%, 29%, 41% and 74%, respectively. Further, the frequency of supratherapeutic levels among patients varied between 3% for pyrazinamide and 60% for isoniazid. In the below-12 years age category, the median plasma maximum concentration and 12 h exposure of moxifloxacin were significantly lower than that of the above-12 years category despite similar weight-adjusted dosing. Age significantly impacted the plasma concentration and exposure of moxifloxacin. The observed frequencies of suboptimal and supratherapeutic concentrations underscore the necessity for dose optimization and therapeutic drug monitoring in children and adolescents undergoing DR-TB treatment.

Adaptive evaluation of mHealth and conventional adherence support interventions to optimize outcomes with new treatment regimens for drug-resistant tuberculosis and HIV in South Africa (ADAP-TIV): study protocol for an adaptive randomized controlled trial

BackgroundHighly effective, short-course, bedaquiline-containing treatment regimens for multidrug-resistant tuberculosis (MDR-TB) and integrase strand transfer inhibitor (INSTI)-containing fixed dose combination antiretroviral therapy (ART) have radically transformed treatment for MDR-TB and HIV. However, without advances in adherence support, we may not realize the full potential of these therapeutics. The primary objective of this study is to compare the effect of adherence support interventions on clinical and biological endpoints using an adaptive randomized platform.MethodsThis is a prospective, adaptive, randomized controlled trial comparing the effectiveness of four adherence support strategies on a composite clinical outcome in adults with MDR-TB and HIV initiating bedaquiline-containing MDR-TB treatment regimens and receiving ART in KwaZulu-Natal, South Africa. Trial arms include (1) enhanced standard of care, (2) psychosocial support, (3) mHealth using cellular-enabled electronic dose monitoring, and (4) combined mHealth and psychosocial support. The level of support will be titrated using a differentiated service delivery (DSD)-informed assessment of treatment support needs. The composite primary outcome will include survival, negative TB culture, retention in care, and undetectable HIV viral load at month 12. Secondary outcomes will include individual components of the primary outcome and quantitative evaluation of adherence on TB and HIV treatment outcomes.DiscussionThis trial will evaluate the contribution of different modes of adherence support on MDR-TB and HIV outcomes with WHO-recommended all-oral MDR-TB regimens and ART in a high-burden operational setting. We will also assess the utility of a DSD framework to pragmatically adjust levels of MDR-TB and HIV treatment support.Trial registrationClinicalTrials.gov NCT05633056. Registered on 1 December 2022

Treating drug-resistant tuberculosis in an era of shorter regimens: Insights from rural South Africa

Background. Progressive interventions have recently improved programmatic outcomes in drug-resistant tuberculosis (DR-TB) care in South Africa (SA). Amidst these, a shorter regimen was introduced in 2017 with weak evidence, and has shown mixed results. Outcomes still fall short of national targets, and the coronavirus disease 2019 pandemic has undermined progress to date. Objectives. To describe the outcomes of participants treated for DR-TB using a shorter, compared with a longer, regimen in a deeply rural SA setting, and to explore other factors affecting these outcomes. Methods. This retrospective cohort study describes outcomes in short and long DR-TB treatment regimens, over 5 years, at two rural treatment sites in SA. Characteristics were analysed for outcome correlates using multivariable logistic regression models. Results. Of 282 treatment episodes, 62% were successful, with higher success in shorter (69%) compared with longer regimens (58%). Mortality was approximately 21% in both groups. Characteristics included high proportions of HIV co-infection (61%). Injectables (adjusted odds ratio (aOR) 3.00, 95% confidence interval (CI) 1.48 - 6.09), bedaquiline (aOR 3.16, 95% CI 1.36 - 7.35), increasing age (aOR 0.97, 95% CI 0.95 - 0.99) and HIV viraemia defined as final HIV-RNA viral load >1 000 copies/mL (aOR 0.16, 95% CI 0.07 - 0.37) were all significantly and independently associated with treatment success. Injectables (aOR 0.22, 95% CI 0.08 - 0.57), bedaquiline (aOR 0.05, 95% CI 0.01 - 0.19), increasing age (aOR 1.09, 95% CI 1.05 - 1.13), extra-pulmonary TB (aOR 8.15, 95% CI 1.62 - 41.03) and HIV viraemia (aOR 9.20, 95% CI 3.22 - 26.24) were all significantly and independently associated with mortality. Conclusion. In a rural context, treating DR-TB amid limited resources and a high burden of HIV co-infection, we found that after considering controls, a short regimen was no different to a longer regimen in terms of success or mortality. Therefore, by alleviating burdens on multiple stakeholders, a short regimen is likely to be favourable for rural patients, clinicians, and healthcare systems. Besides other previously described correlates of outcomes, HIV viraemia emerged as a novel marker for reliably predicting poor outcomes in DR-TB with HIV co-infection, and a pragmatic target for intervention.

Public health benefits of shifting from hospital-focused to ambulatory TB care in Eastern Europe: Optimising TB investments in Belarus, the Republic of Moldova, and Romania.

High rates of drug-resistant tuberculosis (DR-TB) continue to threaten public health, especially in Eastern Europe. Costs for treating DR-TB are substantially higher than treating drug-susceptible TB, and higher yet if DR-TB services are delivered in hospital. The WHO recommends that multidrug-resistant (MDR) TB be treated using mainly ambulatory care, shown to have non-inferior health outcomes, however, there has been a delay to transition away from hospital-focused MDR-TB care in certain Eastern European countries. Allocative efficiency analyses were conducted for three countries in Eastern Europe, Belarus, the Republic of Moldova, and Romania, to minimise a combination of TB incidence, prevalence, and mortality by 2035. A primary focus of these studies was to determine the health benefits and financial savings that could be realised if DR-TB service delivery shifted from hospital-focused to ambulatory care. Here we provide a comprehensive assessment of findings from these studies to demonstrate the collective benefit of transitioning from hospital-focused to ambulatory TB care, and to address common regional considerations. We highlight that transitioning from hospital-focused to ambulatory TB care could reduce treatment costs by 20% in Romania, 24% in Moldova, and by as much as 40% in Belarus or almost 35 million US dollars across these three countries by 2035 without affecting quality of care. Improved TB outcomes could be achieved, however, without additional spending by reinvesting these savings in higher-impact TB diagnosis and more efficacious DR-TB treatment regimens. We found commonalities in the large portion of TB cases treated in hospital across these three regional countries, and similar obstacles to transitioning to ambulatory care. National governments in the Eastern European region should examine barriers delaying adoption of ambulatory DR-TB care and consider lost opportunities caused by delays in switching to more efficient treatment modes.

Serial electrocardiogram recordings revealed a high prevalence of QT interval prolongation in patients with tuberculosis receiving fluoroquinolones

Fluoroquinolones, crucial components of treatment regimens for drug-resistant tuberculosis (TB), are associated with QT interval prolongation and risks of fatal cardiac arrhythmias. However, few studies have explored dynamic changes in the QT interval in patients receiving QT-prolonging agents. This prospective cohort study recruited hospitalized patients with TB who received fluoroquinolones. The study investigated the variability of the QT interval by using serial electrocardiograms (ECGs) recorded four times daily. This study analyzed the accuracy of intermittent and single-lead ECG monitoring in detecting QT interval prolongation. This study included 32 patients. The mean age was 68.6±13.2 years. The results revealed mild-to-moderate and severe QT interval prolongation in 13 (41%) and 5 (16%) patients, respectively. The incremental yields in sensitivity of one to four daily ECG recordings were 61.0%, 26.1%, 5.6%, and 7.3% in detecting mild-to-moderate QT interval prolongation, and 66.7%, 20.0%, 6.7%, and 6.7% in detecting severe QT interval prolongation. The sensitivity levels of lead II and V5 ECGs in detecting mild-to-moderate and severe QT interval prolongation exceeded 80%, and their specificity levels exceeded 95%. This study revealed a high prevalence of QT interval prolongation in older patients with TB who receive fluoroquinolones, particularly those with multiple cardiovascular risk factors. Sparsely intermittent ECG monitoring, the prevailing strategy in active drug safety monitoring programs, is inadequate owing to multifactorial and circadian QT interval variability. Additional studies performing serial ECG monitoring are warranted to enhance the understanding of dynamic QT interval changes in patients receiving QT-prolonging anti-TB agents.

Shorter regimens improved treatment outcomes of multidrug-resistant tuberculosis patients in Tanzania in 2018 cohort.

In 2018, shorter treatment regimens (STR) for people with drug-resistant tuberculosis (DR-TB) were introduced in Tanzania and included kanamycin, high-dose moxifloxacin, prothionamide, high-dose isoniazid, clofazimine, ethambutol and pyrazinamide. We describe treatment outcomes of people diagnosed with DR-TB in a cohort initiating treatment in 2018 in Tanzania. This was a retrospective cohort study conducted at the National Centre of Excellence and decentralised DR-TB treatment sites for the 2018 cohort followed from January 2018 to August 2020. We reviewed data from the National Tuberculosis and Leprosy Program DR-TB database to assess clinical and demographic information. The association between different DR-TB regimens and treatment outcome was assessed using logistic regression analysis. Treatment outcomes were described as treatment complete, cure, death, failure or lost to follow-up. A successful treatment outcome was assigned when the patient achieved treatment completion or cure. A total of 449 people were diagnosed with DR-TB of whom 382 had final treatment outcomes: 268 (70%) cured; 36 (9%) treatment completed; 16 (4%) lost to follow-up; 62 (16%) died. There was no treatment failure. The treatment success rate was 79% (304 patients). The 2018 DR-TB treatment cohort was initiated on the following regimens: 140 (46%) received STR, 90 (30%) received the standard longer regimen (SLR), 74 (24%) received a new drug regimen. Normal nutritional status at baseline [adjusted odds ratio (aOR)=6.57, 95% CI (3.33-12.94), p < 0.001] and the STR [aOR=2.67, 95% CI (1.38-5.18), p=0.004] were independently associated with successful DR-TB treatment outcome. The majority of DR-TB patients on STR in Tanzania achieved a better treatment outcome than on SLR. The acceptance and implementation of STR at decentralised sites promises greater treatment success. Assessing and improving nutritional status at baseline and introducing new shorter DR-TB treatment regimens may strengthen favourable treatment outcomes.

Toxicity of treatment regimens for drugresistant tuberculosis.

Background. The main factors reducing treatment effectiveness in patients with pulmonary tuberculosis are as follows: the growing drug resistance of mycobacteria, which necessitates the strengthening of chemotherapy regimens, the use of new antimicrobial drugs, as well as poor tolerability of treatment due to the high frequency of adverse drug reactions. Combinations of fluoroquinolones, bedaquiline, and linezolid with traditional anti-tuberculosis drugs are used in new regimens for the treatment of patients with multidrug- and extensively drug-resistant tuberculosis, but the safety of new regimens has yet to be sufficiently studied.The aim was to study the features of toxic effect manifestations of the 5-component antimycobacterial drug complexes in an experiment on rats.Methods. The study was carried out on 64 non-pedigree rats, old females, divided equally into 3 experimental groups and 1 control. Rats of the experimental groups received drug complexes at doses corresponding to therapeutic doses for humans. The complexes’ base components were: moxifloxacin, bedaquiline, linezolid, and capreomycin. The fifth drug in group 1 was prothionamide, in the 2nd — pyrazinamide, in the 3rd — cycloserine. After 14 and 28 days of administration, the clinical picture of intoxication, ECG results, behavioral reactions of rats in the open field test, biochemical blood and urine tests, as well as pathomorphological studies were analysed.Results. Progressive damage to the gastrointestinal tract, liver, kidneys, and central nervous system was observed in rats of all experimental groups. The leading reason of polytoxicity is the nephrotoxic effect caused by capreomycin, to which rats have a high species sensitivity. In group 1, rats were treated with three drugs possessing potential cardiotoxicity; cardiotoxic effect was observed in the form of prolongation of the QT interval on the ECG after 14 days of administration. The most toxic combination of drugs was the one used in rats of the 3rd group, it was enhanced by the addition of neurotoxic cycloserine, which led to the death of more than a third of the animals by the end of the experiment.Conclusion: the use of multicomponent combinations of antimycobacterial drugs, similar in safety profile, increases the risk of developing combined toxic reactions.

Comparative Performance of Genomic Methods for the Detection of Pyrazinamide Resistance and Heteroresistance in Mycobacterium tuberculosis.

ABSTRACTPyrazinamide is an important component of both drug-susceptible and drug-resistant tuberculosis treatment regimens. Although approximately 50% of rifampin-resistant isolates are also resistant to pyrazinamide, pyrazinamide susceptibility testing is not routinely performed due to the challenging nature of the assay. We investigated the diagnostic accuracy of genotypic and phenotypic methods and explored the occurrence of pyrazinamide heteroresistance. We assessed pyrazinamide susceptibility among 358 individuals enrolled in the South African EXIT-RIF cohort using Sanger and targeted deep sequencing (TDS) of the pncA gene, whole-genome sequencing (WGS), and phenotypic drug susceptibility testing. We calculated the diagnostic accuracy of the different methods and investigated the prevalence and clinical impact of pncA heteroresistance. True pyrazinamide susceptibility status was assigned to each isolate using the Köser classification and expert rules. We observed 100% agreement across genotypic methods for detection of pncA fixed mutations; only TDS confidently identified three isolates (0.8%) with minor variants. For the 355 (99.2%) isolates that could be assigned true pyrazinamide status with confidence, phenotypic DST had a sensitivity of 96.5% (95% confidence interval [CI], 93.8 to 99.3%) and specificity of 100% (95% CI, 100 to 100%), both Sanger sequencing and WGS had a sensitivity of 97.1% (95% CI, 94.6 to 99.6%) and specificity of 97.8% (95% CI, 95.7 to 99.9%), and TDS had sensitivity of 98.8% (95% CI, 97.2 to 100%) and specificity of 97.8% (95% CI, 95.7 to 99.9%). We demonstrate high sensitivity and specificity for pyrazinamide susceptibility testing among all assessed genotypic methods. The prevalence of pyrazinamide heteroresistance in Mycobacterium tuberculosis isolates was lower than that identified for other first-line drugs.

Drug Resistant Tuberculosis and Pharmacovigilance –an Indian Perspective

Drug-resistant tuberculosis (DR-TB) continues to be a public health problem. The emergence of resistance to antitubercular drugs, particularly those for treatment of DR-TB, has complicated the treatment with prolonged duration, and a higher risk of adverse effects (AEs). Introduction of newer drugs in DR-TB treatment regimens, co-morbid conditions, concomitant drugs and specific populations, increase the risk of previously unrecognized AEs and can contribute to unfavorable treatment outcomes. The Pharmacovigilance programme of India (PvPI) has been focusing on monitoring and management of ADRs associated with bedaquiline and delamanid along with other anti-tubercular drugs. This article will discuss the need, process of monitoring of adverse events for these drugs in India and a need to increase awareness among the general public.

Preparedness of outpatient health facilities for ambulatory treatment with all-oral short DR-TB treatment regimens in Zhytomyr, Ukraine: a cross-sectional study

BackgroundUkraine has a high burden of drug-resistant tuberculosis (DR-TB). Mental health problems, including alcohol use disorder, are common co-morbidities. One in five DR-TB patients has human immunodeficiency virus (HIV). As part of health reform, the country is moving from inpatient care to ambulatory primary care for tuberculosis (TB). In Zhytomyr oblast, Médecins Sans Frontières (MSF) is supporting care for DR-TB patients on all-oral short DR-TB regimens. This study describes the preparedness of ambulatory care facilities in Zhytomyr oblast, Ukraine, to provide good quality ambulatory care.MethodsThis is a retrospective analysis of routinely collected programme data. Before discharge of every patient from the hospital, MSF teams assess services available at outpatient facilities using a standardised questionnaire. The assessment evaluates access, human resources, availability of medicines, infection control measures, laboratory and diagnostic services, and psychosocial support.ResultsWe visited 68 outpatient facilities in 22 districts between June 2018 and September 2019. Twenty-seven health posts, 24 TB-units, 13 ambulatories, two family doctors and one polyclinic, serving 30% of DR-TB patients in the oblast by September 2019, were included. All facilities provided directly observed treatment, but only seven (10%) provided weekend-services. All facilities had at least one medical staff member, but TB-training was insufficient and mostly limited to TB-doctors. TB-treatment and adequate storage space were available in all facilities, but only five (8%) had ancillary medicines. HIV-positive patients had to visit a separate facility to access HIV-care. Personal protective equipment was unavailable in 32 (55%) facilities. Basic laboratory services were available in TB-units, but only four (17%) performed audiometry. Only ten (42%) TB-units had psychosocial support available, and nine (38%) offered psychiatric support.ConclusionOutpatient facilities in Zhytomyr oblast are not yet prepared to provide comprehensive care for DR-TB patients. Capacity of all facilities needs strengthening with trainings, infection control measures and infrastructure. Integration of psychosocial services, treatment of co-morbidities and adverse events at the same facility are essential for successful decentralisation. The health reform is an opportunity to establish quality, patient-centred care.

Long-term impact of the adoption of bedaquiline-containing regimens on the burden of drug-resistant tuberculosis in China

BackgroundCurrently available injectable agents are inadequate to address the high drug-resistant tuberculosis (DR-TB) burden in China. Regimens including the oral agent bedaquiline have been shown to be efficacious and safe, leading to its incorporation into multiple national TB treatment programs. This analysis evaluated the impact of increased adoption of bedaquiline-containing regimens on the DR-TB burden in China.MethodsA state-transition model was developed that permits movement and interaction between susceptible, latent, and active TB disease states, while distinguishing between drug-sensitive (DS) and DR-TB. Model inputs were obtained from the published literature or derived such that model metrics approximated those published by the WHO. Expected improvements in infrastructure were built into the model to forecast the epidemiology of DR-TB in China through 2040 in the absence of bedaquiline (baseline forecast). The impact of higher utilization of bedaquiline-containing regimens (85% peak share) was then assessed in two scenarios that differed with regard to treatment success rates of the regimens: 61% (reflecting findings of clinical trials) and 80% (reflecting data from observational studies), versus the 44% success rate associated with standard-of-care treatment.ResultsIn the baseline scenario, the model predicted increases in annual incidence of DR-TB by 6–8% during each five-year period between 2020 and 2040, with an increase of 30% over the entire study duration. Adoption of bedaquiline-based regimens limits the incidence increases to only 1–3% in each five-year period and to 8% over the study duration in the 61% success rate scenario. Incidence declines by 1–6% during each five-year period and by 12% over the study duration in the 80% success rate scenario. Similar effects on DR-TB prevalence (4–5% increase in baseline, 0–7% decline in scenario 1, and 4–19% decline in scenario 2) and mortality (5–7% increase in baseline, 0–16% decline in scenario 1, and 6–40% decline in scenario 2) were seen following bedaquiline adoption.ConclusionsIncorporation of bedaquiline into DR-TB treatment regimens will significantly reduce the DR-TB burden in China, helping to counter the expected increase in burden in the absence of bedaquiline. The study will provide valuable information to public health policy planners.

1884. Clinical Outcomes Among Patients with Drug-Resistant Tuberculosis Receiving Bedaquiline or Delamanid Containing Regimens

BackgroundBedaquiline and delamanid are new and much-needed treatment options for drug-resistant tuberculosis (TB); however, there are limited data guiding their use and no direct comparison of the two drugs. We thus sought to compare the clinical outcomes of patients with drug-resistant tuberculosis receiving either a bedaquiline- or delamanid-based treatment regimen.MethodsThis is a prospective observational study among patients with drug-resistant pulmonary TB in the country of Georgia from 2015 to 2017. Patients receiving bedaquiline or delamanid were eligible to be enrolled. Monthly sputum cultures and MIC testing on Mycobacterium tuberculosis isolates were performed. Clinical outcomes included time to culture conversion, rate of acquired drug resistance and treatment outcomes.ResultsAmong 156 patients with MDR-TB who were approached, 100 were enrolled, and 95 were receiving a bedaquiline (n = 64) or delamanid (n = 31) based regimen and included in the study. Patients receiving bedaquiline or delamanid were similar with regards to age, BMI, substance use, comorbidities, rate of cavitary disease, and extensively drug-resistant (XDR) TB. Rates of additional Class A drug use including linezolid (78 vs. 81%) and a fluoroquinolone (39 vs. 36%) were similar and the mean effective drugs received per group was 4 (IQR 3–4, P = 0.33). Median drug duration was 171 days for bedaquiline and 182 days for delamanid; no patient discontinued due to QTC prolongation. Adjusted cumulative culture conversion rates at 60 days (64% vs. 48%, P = 0.14) and 180 days (95% vs. 77%, P = 0.02) were higher in patients receiving bedaquiline compared with delamanid (see figure). Rates of acquired drug resistance were higher in patients receiving delamanid compared with bedaquiline (35 vs. 12%, P < 0.01). Lastly, patients receiving a bedaquiline-based regimen had higher rates of favorable outcomes as compared with patients receiving delamanid (94% vs. 67%, P < 0.01).ConclusionPatients receiving bedaquiline- and delamanid-based treatment regimens for drug-resistant TB had similar characteristics and those receiving bedaquiline had better clinical outcomes. Our results provide an important first comparison of bedaquiline vs. delamanid containing regimens. Disclosures All Authors: No reported Disclosures.

Surveillance of adverse events in the treatment of drug-resistant tuberculosis: A global feasibility study

The World Health Organization launched a global initiative, known as aDSM (active TB drug safety monitoring and management) to better describe the safety profile of new treatment regimens for drug-resistant tuberculosis (TB) in real-world settings. However, comprehensive surveillance is difficult to implement in several countries.The aim of the aDSM project is to demonstrate the feasibility of implementing national aDSM registers and to describe the type and the frequency of adverse events (AEs) associated with exposure to the new anti-TB drugs.Following a pilot study carried out in 2016, official involvement of TB reference centres/countries into the project was sought and cases treated with bedaquiline- and/or delamanid-containing regimens were consecutively recruited. AEs were prospectively collected ensuring potential attribution of the AE to a specific drug based on its known safety profile.A total of 309 cases were fully reported from 41 centres in 27 countries (65% males; 268 treated with bedaquiline, 20 with delamanid, and 21 with both drugs) out of an estimated 781 cases the participating countries had committed to report by the first quarter of 2019.

Linezolid Pharmacokinetics in South African Patients with Drug-Resistant Tuberculosis and a High Prevalence of HIV Coinfection.

The World Health Organization (WHO) recently recommended that linezolid be prioritized in treatment regimens for drug-resistant tuberculosis (TB), but there are limited data on its pharmacokinetics (PK) in patients with this disease. We conducted an observational study to explore covariate effects on linezolid PK and to estimate the probability of PK/pharmacodynamic target attainment in South African patients with drug-resistant TB. Consecutive adults on linezolid-based regimens were recruited in Cape Town and underwent intensive PK sampling at steady state. Noncompartmental analysis was performed. Thirty participants were included: 15 HIV positive, 26 on the initial dose of 600 mg daily, and 4 participants on 300 mg daily after dose reduction for linezolid-related toxicity. There was a negative correlation between body weight and exposure, with 17.4% (95% confidence interval [CI], 0.1 to 31.7) decrease in area under the concentration-time curve from 0 to 24 h (AUC0-24) per 10-kg weight increment after adjustment for other covariates. Age was an independent predictor of trough concentration, with an estimated 43.4% (95% CI, 5.9 to 94.2) increase per 10-year increment in age. The standard 600-mg dose achieved the efficacy target of free AUC/MIC of >119 at wild-type MIC values (≤0.5 mg/liter), but the probability of target attainment dropped to 61.5% (95% CI, 40.6 to 79.8) at the critical concentration of 1 mg/liter. When dosed at 600 mg daily, trough concentrations were above the toxicity threshold of 2 mg/liter in 57.7% (95% CI, 36.9 to 76.6). This confirms the narrow therapeutic index of linezolid, and alternative dosing strategies should be explored.

Promising shorter and more effective treatment regimens for drug-resistant tuberculosis: recent research found

Promising shorter and more effective treatment regimens for drug-resistant tuberculosis: recent research found

Linezolid in South Africa: The regulatory authority’s role in supporting access to improved treatment regimens for drug-resistant tuberculosis

The rising incidence of drug-resistant tuberculosis (DR-TB) in South Africa is cause for concern, with doctors having limited treatment options to offer patients who face excruciating side-effects from existing medications, and poor odds of treatment success. With several newer drugs showing efficacy against DR-TB, increased possibilities exist to stem the tide of the epidemic, shorten treatment duration, and improve outcomes. To take advantage of this potential TB treatment revolution, countries must rapidly facilitate access to existing and future drugs. This requires co-ordinated action from governments, and particularly regulatory authorities, in promoting early access to new treatments, tackling intellectual property and price barriers, expediting regulatory approval, adopting and implementing up-to-date TB management policies, and engaging with research and development processes for new regimens. Doctors Without Borders expended great effort to obtain a less expensive version of the drug, linezolid, for its DR-TB pilot program in Khayelitsha, South Africa. This piece describes that experience, and subsequently offers recommendations for policy reforms which could help South Africa more rapidly access other new TB drugs in the future. The South African experience may be of relevance to other countries seeking advice on how to facilitate access to new treatments and tackle their TB epidemics.

1474Genotypic Characterization of pncA Gene in Patients with Multidrug-resistant Tuberculosis from South Africa

Rationale: Pyrazinamide (PZA) is an essential component of empiric firstand second-line tuberculosis (TB) treatment regimens. However, PZA drug susceptibility testing (DST) is difficult to perform and not routinely available. Genetic mutations in the pncA gene of Mycobacterium tuberculosis (Mtb) commonly confer PZA resistance, but limited data on the prevalence and diversity of these mutations are available from clinical populations of TB patients. We sequenced pncA to estimate PZA resistance among MDR and XDR TB patients in KwaZulu-Natal province, South Africa. Methods: We prospectively enrolled 206 MDR TB and 377 XDR TB patients from September 2011 to September 2014. Sputum collected from each participant underwent mycobacterial culture and DST for isoniazid (H), rifampin (R), streptomycin (S), kanamycin (Km) and ofloxocin (Ofx). We extracted DNA from pure Mtb isolates and performed targeted sequencing of the pncA gene, characterizing the proportion, frequency and structure of polymorphisms. Results: To date, targeted sequencing has been completed for 314 isolates from 80 MDR TB (16 resistant to HR 20 different mutations were seen among MDR TB subjects, of which, only 7 were seen in more than one participant. Among XDR TB participants, one mutation (insertion of cytosine after the 456 locus) was present in 166 (71%), consistent with the clonality of XDR TB patients in KwaZulu-Natal. Conclusion: Nearly 70% of MDR TB and nearly all XDR TB participants had pncA mutations, and likely PZA resistance, in our cohort. A wide diversity of mutations was seen. Most mutations were singlets, suggesting acquisition of mutations de novo, perhaps due to empiric use. One specific mutation was common among XDR TB participants, but it occurred in conjunction with a specific RFLP genotype associated with clonal expansion. Given the difficulty in determining PZA susceptibility, characterizing pncA mutations may provide important data for developing rapid genotypic PZA susceptibility assays. BACKGROUND • South Africa has one of the highest incidence rates of multidrug-resistant tuberculosis (MDR TB) and extensively drug-resistant tuberculosis (XDR TB) with high rates of HIV co-infection. • Pyrazinamide (PZA) is used empirically in drug-resistant TB treatment regimens. • Precise acidic conditions are required in vitro to conduct PZA drug susceptibility testing (DST). However, acidic environments inhibit the growth of Mycobacterium tuberculosis (Mtb) bacilli. • Therefore, conventional PZA DST is difficult to perform in vitro and not widely available. • Gene sequencing is an effective method to identify mutations associated with resistance for some firstand second-line anti-TB drugs. • Genetic mutations in the pncA gene of Mtb typically confer resistance to PZA. However data on the frequency and diversity of pncA mutations is limited. • Thus, the actual prevalence of PZA resistance in patients with TB and drug-resistant TB is unknown. Funding: NIH/NIAID R01AI087465 [PI Neel Gandhi] and NIH/NIAID R01AI089349 [PI Neel Gandhi] Contact: Salim Allana, MD, MPH; salim.allana@emory.edu SETTING • Study site: KwaZulu-Natal province, South Africa, which has a population of 10.2 million. • TB incidence rate is nearly 1,100 per 100,000 population, and more than 80% of TB cases are HIV co-infected. • In 2012, MDR TB incidence was 45 cases/100,000 population and XDR TB incidence was 3.1 cases/100,000 population. • The HIV prevalence among adults (15-49 years of age) is 16.8%. • MDR TB patients receive standardized second-line treatment which includes PZA, ethambutol, kanamycin, moxifloxacin, terizidone, and ethionamide. • XDR TB patients receive a similar regimen, except that capreomycin, moxifloxacin and PAS replace kanamycin. • DST testing to evaluate PZA susceptibility is not routinely performed in this setting. OBJECTIVE Among MDR and XDR TB subjects in KwaZulu-Natal province, South Africa: • To characterize the frequency and diversity of polymorphisms in the pncA gene. • To estimate the prevalence of pyrazinamide resistance.

Effects of two treatment regimens for drug-resistant tuberculosis in tuberculosis control project areas: a comparative study

To search for an ideal therapeutic regimen for multidrug resistant tuberculosis conforming to the situation of China. One hundred and fifty-four patients with rifampin-resistant tuberculosis, 114 multi-drug resistant (MDR-TB) and 40 resistant to other drugs, in Heilongjiang, Zhejiang, and Shenzhen, 107 males and 47 females, aged 39 (19-77), were randomly divided into 2 groups: 85 patients in the group of drug-resistant regimen, 3RFT AM Ofx Pto PAS-INH/5RFT Ofx Pto PAS-INH regimen, including rifapentine (RFT), amikacin (Am), ofloxacin (Ofx), protionamide (Pto), para-aminosalicylic acid-isoniazid (PAS-INH) for 3 months and then RFT, Ofx, Pto, and PAS-INH for 5 months, and 69 in the retreatment regimen group undergoing 3 H3R3Z3E3S3/5 H3R3E3, including isoniazid (H), rifampin (R), pyrazinamide (Z), ethambutol (E), and streptomycin (S) for 3 months and then H, R, and E for 5 months. Sputum smear was checked and the sputum smear conversion rate was calculated as an effective treatment indicator 3, 6, and 8 months later. One hundred and fourteen of the 154 patients were treated for a good 8 months. The sputum smear conversion rate 8 months after treatment of the drug-resistant regimen group was 65.9% (56/85), significantly higher than that of the retreatment regimen group [40.6% (28/69), chi2 = 9.834, P = 0.002]. Eighty-five of the 114 MDR-TB patients had been treated for a good 8 months with a sputum smear conversion rate of 61.8% (42/68), significantly higher than that of the retreatment regimen group [39.1% (18/46), chi2 = 5.638, P = 0.018]. Sputum smear conversion at the end of the 8th month was related to age, course of disease, therapeutic regimen, and the type of drug-resistance (all P < 0.05). The side-effect rate of the drug-resistant regimen group was 23.9% (17/71), higher than that of the retreatment regimen group [18.6% (8/43)], but not significantly (chi2 = 0.446, P = 0.504). The drug-resistant regimen recommended above is more effective than the retreatment regimen and should be considered in the areas where the WHO guideline fails to be followed or drug sensitivity test (DST) cannot be conducted and adjusted according to the results of DST and treatment.