Long-term outcome and safety of prolonged bedaquiline treatment for multidrug-resistant tuberculosis

Bedaquiline, a recently approved drug for the treatment of multidrug-resistant tuberculosis (MDR-TB), is recommended for a duration of 24 weeks. There are scarce data on patients treated with this drug outside clinical trials.All MDR-TB patients who started treatment from January 1, 2011 to December 31, 2013 and received ≥30 days of bedaquiline were included in a multicentre observational cohort.Among 45 MDR-TB patients, 53% harboured isolates resistant to both fluoroquinolones and second-line injectables, and 38% harboured isolates resistant to one of these drug classes. Median bedaquiline treatment duration was 361 days and 33 patients (73%) received prolonged (>190 days) bedaquiline treatment. Overall, 36 patients (80%) had favourable outcome, five were lost to follow-up, three died, and one failed and acquired bedaquiline resistance. No cases of recurrence were reported. Severe and serious adverse events were recorded in 60% and 18% of patients, respectively. Values of Fridericia-corrected QT interval (QTcF) >500 ms were recorded in 11% of patients, but neither arrhythmias nor symptomatic cardiac side-effects occurred. Bedaquiline was discontinued in three patients following QTcF prolongation. No significant differences in outcomes or adverse events rates were observed between patients receiving standard and prolonged bedaquiline treatment.Bedaquiline-containing regimens achieved favourable outcomes in a large proportion of patients. Prolonged bedaquiline treatment was overall well tolerated in this cohort.

Download Full-text

Active surveillance for adverse events in patients on longer treatment regimens for multidrug-resistant tuberculosis in Viet Nam

PLoS ONE ◽

10.1371/journal.pone.0255357 ◽

2021 ◽

Vol 16 (9) ◽

pp. e0255357

Author(s):

Nguyen Bao Ngoc ◽

Hoa Vu Dinh ◽

Nguyen Thi Thuy ◽

Duong Van Quang ◽

Cao Thi Thu Huyen ◽

...

Keyword(s):

Risk Factors ◽

Adverse Events ◽

Bayesian Model Averaging ◽

Multidrug Resistant ◽

Treatment Regimens ◽

Tb Treatment ◽

Resistant Tuberculosis ◽

Multidrug Resistant Tuberculosis ◽

Mdr Tb

Objective Management of multidrug-resistant tuberculosis (MDR-TB) is a significant challenge to the global healthcare system due to the complexity and long duration of the MDR-TB treatment. This study analyzed the safety of patients on longer injectable-based MDR-TB treatment regimens using active pharmacovigilance data. Method We conducted an observational, prospective study based on active pharmacovigilance within the national TB program. A total of 659 MDR-TB patients were enrolled and followed up at 9 TB- hospitals in 9 provinces of all 3 regions in Vietnam between 2014 and 2016. Patients received a treatment regimen (standardized or individualized) based on their drug susceptibility test result and their treatment history. Baseline and follow-up information was collected at the start and during treatment. Adverse events (AE) were defined and classified as serious adverse events (SAEs) or otherwise. Multivariate Cox regression following the Iterative Bayesian Model Averaging algorithm was performed to identify factors associated with AE occurrence. Results Out of 659 patients assessed, 71.3% experienced at least one AE, and 17.5% suffered at least one SAE. The most common AEs were gastrointestinal disorders (38.5%), arthralgia (34.7%), and psychiatric disorders (30.0%). The proportion of patients with nephrotoxicity and hearing loss or vestibular disorders were 7.4% and 15.2%, respectively. 13.1% of patients required modifications or interruption of one or more drugs. In 77.7% of patients, treatment was completed successfully, while 9.3% lost to follow-up, in 3.0% treatment failed, and 7.4% died. Some significant risk factors for nephrotoxicity included diabetes mellitus (HR = 8.46 [1.91–37.42]), renal dysfunction (HR = 8.46 [1.91–37.42]), alcoholism (HR = 13.28 [5.04–34.99]), and a higher average daily dose of injectable drugs (HR = 1.28 [1.14–1.43]). Conclusion While a majority of patients on the longer injectable-based regimens experienced non-serious AEs during MDR-TB treatment, one in six patients experienced at least an SAE. Active TB drug-safety monitoring is useful to understand the safety of MDR-TB treatment and explore the risk factors for toxicity. All-oral, shorter MDR-TB regimens might be able to reduce the inconvenience, discomfort, and toxicity of such regimens and increase adherence and likelihood of successful completion.

Download Full-text

Randomized Pilot Trial of Eight Weeks of Bedaquiline (TMC207) Treatment for Multidrug-Resistant Tuberculosis: Long-Term Outcome, Tolerability, and Effect on Emergence of Drug Resistance

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.06126-11 ◽

2012 ◽

Vol 56 (6) ◽

pp. 3271-3276 ◽

Cited By ~ 217

Author(s):

A. H. Diacon ◽

P. R. Donald ◽

A. Pym ◽

M. Grobusch ◽

R. F. Patientia ◽

...

Keyword(s):

Pilot Trial ◽

Acquired Resistance ◽

Multidrug Resistant ◽

Controlled Study ◽

Noncardiac Chest Pain ◽

Term Outcome ◽

Long Term Outcome ◽

Resistant Tuberculosis ◽

Multidrug Resistant Tuberculosis

ABSTRACTThe 2-year follow-up results for a randomized placebo-controlled study of 47 patients with multidrug-resistant pulmonary tuberculosis treated with either the new diarylquinoline TMC207, recently renamed bedaquiline, or placebo, added to the first 8 weeks of a background regimen, are presented. Bedaquiline significantly reduced the time to culture conversion over 24 weeks (hazard ratio, 2.253; 95% confidence interval, 1.08 to 4.71;P= 0.031). With the exception of nausea reported in 26% of patients receiving bedaquiline and none receiving placebo, adverse events occurred at similar frequencies in both groups of patients: bilateral hearing impairment, extremity pain, acne, and noncardiac chest pain occurred in 13 and 21%, 17 and 13%, 9 and 17%, and 4 and 17% of patients, respectively, receiving bedaquiline or placebo. Excluding resistance to ethambutol and ethionamide, only one patient receiving bedaquiline acquired resistance to companion drugs, but five patients receiving placebo (4.8% versus 21.7%;P= 0.18) acquired resistance to companion drugs, and resistance to ofloxacin was acquired in four patients receiving placebo and none receiving bedaquiline (0% versus 22%; 0 = 0.066). In all, 23 patients (49%), including 13 receiving placebo (54%) and 10 receiving bedaquiline (44%), discontinued the study prior to its completion, 12 during the first 24 weeks of treatment. Eight subjects were withdrawn for noncompliance or default, and seven withdrew consent, citing the rigorous program of investigations for safety and pharmacokinetic monitoring. Bedaquiline may contribute to the management of multidrug-resistant tuberculosis by effecting more rapid sputum culture negativity and by preventing acquired resistance to companion drugs.

Download Full-text

Outcomes with a shorter multidrug-resistant tuberculosis regimen from Karakalpakstan, Uzbekistan

ERJ Open Research ◽

10.1183/23120541.00537-2020 ◽

2020 ◽

pp. 00537-2020

Author(s):

Philipp du Cros ◽

Khamraev Atadjan ◽

Tigay Zinaida ◽

Tleubergen Abdrasuliev ◽

Jane Greig ◽

...

Keyword(s):

Treatment Failure ◽

Treatment Success ◽

Multidrug Resistant ◽

Drug Susceptibility Testing ◽

Fluoroquinolone Resistance ◽

Second Line ◽

Serious Adverse Events ◽

Resistant Tuberculosis ◽

Multidrug Resistant Tuberculosis ◽

Mdr Tb

BackgroundIn 2016, WHO guidelines conditionally recommended standardised shorter 9–12 month regimens for multidrug-resistant tuberculosis (MDR-TB) treatment. We conducted a prospective study of a shorter standardised MDR-TB regimen in Karakalpakstan, Uzbekistan.MethodsConsecutive adults and children with confirmed rifampicin-resistant pulmonary TB were enrolled between 1st September 2013 and 31st March 2015; exclusions included prior treatment with second-line anti-TB drugs, and documented resistance to ofloxacin or to two second-line injectable agents. The primary outcome was recurrence-free cure at 1 year following treatment completion.ResultsOf 146 enrolled, 128 patients were included: 67 female (52.3%), median age 30.1 (IQR 23.8–44.4) years. At the end of treatment, 71.9% (92/128) patients achieved treatment success, with 68% (87/128) achieving recurrence-free cure at 1 year following completion. Unsuccessful outcomes during treatment included 22 (17.2%) treatment failure with fluoroquinolone resistance amplification in 8 patients (8/22, 36.4%); 12 (9.4%) loss to follow-up; 2 (1.5%) deaths. Recurrence occurred in one patient. 14 patients (10.9%) experienced serious adverse events. Baseline resistance to both pyrazinamide and ethambutol (aOR 6.13, 95% CI 2.01;18.63) and adherence<95% (aOR 5.33, 95% CI 1.73;16.36) were associated with unsuccessful outcome in multivariable logistic regression.ConclusionsOverall success with a standardised shorter MDR-TB regimen was moderate with considerable treatment failure and amplification of fluoroquinolone resistance. When introducing standardised shorter regimens, baseline drug susceptibility testing and minimising missed doses are critical. High rates globally of pyrazinamide, ethambutol and ethionamide resistance raise questions of continued inclusion of these drugs in shorter regimens in the absence of DST-confirmed susceptibility.

Download Full-text

Bedaquiline for the Treatment of Multidrug-resistant Tuberculosis in the United States

Clinical Infectious Diseases ◽

10.1093/cid/ciz914 ◽

2019 ◽

Vol 71 (4) ◽

pp. 1010-1016 ◽

Cited By ~ 5

Author(s):

Sundari Mase ◽

Terence Chorba ◽

Samuel Parks ◽

Ann Belanger ◽

Felicia Dworkin ◽

...

Keyword(s):

Adverse Events ◽

Private Insurance ◽

Case Series ◽

The United States ◽

Multidrug Resistant ◽

Qtc Prolongation ◽

Resistant Tuberculosis ◽

Multidrug Resistant Tuberculosis ◽

Mdr Tb ◽

Culture Conversion

Abstract Background In 2012, the Food and Drug Administration approved use of bedaquiline fumarate as part of combination therapy for multidrug-resistant tuberculosis (MDR TB). We describe treatment outcomes, safety, and tolerability of bedaquiline in our case series. Methods Data on patients started on bedaquiline for MDR TB between September 2012 and August 2016 were collected retrospectively through 4 TB programs using a standardized abstraction tool. Data were analyzed using univariate methods. Adverse events were graded using the Common Terminology Criteria for Adverse Events. Results Of 14 patients, 7 (50%) had MDR, 4 (29%) had pre–extensively drug-resistant (XDR), and 3 (21%) had XDR TB. All had pulmonary TB, 5 (36%) had pulmonary and extrapulmonary TB, and 9/13 (69%) were smear positive. One patient (7%) had HIV coinfection, 5 (36%) had diabetes mellitus, and 5/14 (36%) had previous treatment TB. All patients were non–US-born and 5/14 (36%) had private insurance. All patients achieved sputum culture conversion within a mean of 71 days (26–116); 5 after starting bedaquiline. Twelve (86%) completed treatment and 1 (7%) moved out of the country. One patient (7%) had QTc prolongation >500 milliseconds and died 20 months after discontinuing bedaquiline of a cause not attributable to the drug. Common adverse events were peripheral neuropathy 7/14 (50%), not customarily associated with bedaquiline use, and QTc prolongation 6/14 (43%). Conclusions Of 14 patients, 1 (7%) had an adverse event necessitating bedaquiline discontinuation. Safety, culture conversion, and treatment completion in this series (7%) support use of bedaquiline for the treatment of MDR/XDR TB.

Download Full-text

Short-Course Regimen for Multidrug-Resistant Tuberculosis: A Decade of Evidence

Journal of Clinical Medicine ◽

10.3390/jcm9010055 ◽

2019 ◽

Vol 9 (1) ◽

pp. 55 ◽

Cited By ~ 7

Author(s):

Arnaud Trébucq ◽

Tom Decroo ◽

Armand Van Deun ◽

Alberto Piubello ◽

Chen-Yuan Chiang ◽

...

Keyword(s):

Adverse Events ◽

Low Income ◽

Essential Medicine ◽

Multidrug Resistant ◽

World Health ◽

Low Income Countries ◽

Resistant Tuberculosis ◽

Multidrug Resistant Tuberculosis ◽

Mdr Tb ◽

Health Organization

About ten years ago, the first results of the so-called “Bangladesh regimen”, a short regimen lasting nine months instead of 20 months, revolutionized multidrug-resistant tuberculosis (MDR-TB) treatment. Similar short regimens were studied in different settings, relying for their efficacy on a later generation fluoroquinolone, either gatifloxacin, moxifloxacin, or levofloxacin. We review the published material on short MDR-TB regimens, describe their different compositions, their results in national tuberculosis programs in middle- and low-income countries, the risk of acquiring resistance to fluoroquinolone, and the occurrence of adverse events. With over 80% success, the regimen performs much better than longer regimens (usually around 50%). Monitoring of adverse events allows adapting its composition to prevent severe adverse events such as deafness. We discuss the current applicability and usefulness of the short injectable-containing regimen given the 2019 recommendation of the World Health Organization (WHO) for a new long all-oral regimen. We conclude that the most effective fluoroquinolone is gatifloxacin, currently not listed as an essential medicine by WHO. It is a priority to restore its status as an essential medicine.

Download Full-text

Effectiveness and safety of clofazimine in multidrug-resistant tuberculosis: a nationwide report from Brazil

European Respiratory Journal ◽

10.1183/13993003.02445-2016 ◽

2017 ◽

Vol 49 (3) ◽

pp. 1602445 ◽

Cited By ~ 40

Author(s):

Margareth Dalcolmo ◽

Regina Gayoso ◽

Giovanni Sotgiu ◽

Lia D'Ambrosio ◽

Jorge L. Rocha ◽

...

Keyword(s):

Adverse Events ◽

Multidrug Resistant ◽

Success Rates ◽

Loss To Follow Up ◽

Tb Treatment ◽

Resistant Tuberculosis ◽

Multidrug Resistant Tuberculosis ◽

Daily Dose ◽

Mdr Tb

Although clofazimine is used to treat multidrug-resistant tuberculosis (MDR-TB), there is scant information on its effectiveness and safety. The aim of this retrospective, observational study was to evaluate these factors as well as the tolerability of clofazimine in populations in Brazil, where it was administered at a daily dose of 100 mg·day−1 (body weight ≥45 kg) as part of a standardised MDR-TB treatment regimen until 2006 (thereafter pyrazinamide was used).All MDR-TB patients included in the Sistema de Informação de Tratamentos Especiais da Tuberculose (SITETB) individual electronic register were analysed. The effectiveness of clofazimine was assessed by comparing the treatment outcomes of patients undergoing clofazimine-containing regimens against those undergoing clofazimine-free regimens and its safety by describing clofazimine-attributed adverse events. A total of 1446 patients were treated with clofazimine-containing regimens and 1096 with pyrazinamide-containing regimens.Although success rates were similar in patients treated with clofazimine versus those treated with pyrazinamide (880 out of 1446, 60.9%, versus 708 out of 1096, 64.6%; p=0.054), clofazimine-treated cases exhibited higher death rates due to tuberculosis than pyrazinamide-treated ones (314 out of 1446, 21.7%, versus 120 out of 1096, 10.9%) but fewer failures (78 out of 1446, 5.4%, versus 95 out of 1096, 8.7%) and less loss to follow-up (144 out of 1446, 10.0%, versus 151 out of 1096, 13.8%). No relevant differences were detected when comparing adverse events in patients treated with clofazimine-containing regimens to those treated with clofazimine-free regimens. However, the incidence of side-effects was less than previously reported (gastro-intestinal complaints: 10.5%; hyper-pigmentation: 50.2%; neurological disturbances: 9–13%).

Download Full-text

Efficacy and safety of World Health Organization group 5 drugs for multidrug-resistant tuberculosis treatment

European Respiratory Journal ◽

10.1183/13993003.00649-2015 ◽

2015 ◽

Vol 46 (5) ◽

pp. 1461-1470 ◽

Cited By ~ 30

Author(s):

Nicholas Winters ◽

Guillaume Butler-Laporte ◽

Dick Menzies

Keyword(s):

World Health Organization ◽

Multidrug Resistant ◽

World Health ◽

Prolonged Treatment ◽

Serious Adverse Events ◽

Resistant Tuberculosis ◽

Multidrug Resistant Tuberculosis ◽

Mdr Tb ◽

Group 5 ◽

Health Organization

The efficacy and toxicity of several drugs now used to treat multidrug-resistant tuberculosis (MDR-TB) have not been fully evaluated.We searched three databases for studies assessing efficacy in MDR-TB or safety during prolonged treatment of any mycobacterial infections, of drugs classified by the World Health Organization as having uncertain efficacy for MDR-TB (group 5).We included 83 out of 4002 studies identified. Evidence was inadequate for meropenem, imipenem and terizidone. For MDR-TB treatment, clarithromycin had no efficacy in two studies (risk difference (RD) −0.13, 95% CI −0.40–0.14) and amoxicillin–clavulanate had no efficacy in two other studies (RD 0.07, 95% CI −0.21–0.35). The largest number of studies described prolonged use for treatment of non-tuberculous mycobacteria. Azithromycin was not associated with excess serious adverse events (SAEs). Clarithromycin was not associated with excess SAEs in eight controlled trials in HIV-infected patients (RD 0.00, 95% CI −0.02–0.02), nor in six uncontrolled studies in HIV-uninfected patients, whereas six uncontrolled studies in HIV-infected patients clarithromycin caused substantial SAEs (proportion 0.20, 95% CI 0.12–0.27).For most group 5 drugs we found inadequate evidence of safety for prolonged use or for efficacy for MDR-TB, although macrolides appeared to be safe in prolonged use.

Download Full-text

Multidrug-Resistant Tuberculosis: Long Term Follow-Up of 40 Non-HIV-Infected Patients

Canadian Respiratory Journal ◽

10.1155/2000/457905 ◽

2000 ◽

Vol 7 (5) ◽

pp. 383-389 ◽

Cited By ~ 19

Author(s):

Monica Avendaño ◽

RS Goldstein

Keyword(s):

Multidrug Resistant ◽

Inpatient Service ◽

Aminosalicylic Acid ◽

Long Term Outcome ◽

Resistant Tuberculosis ◽

Multidrug Resistant Tuberculosis ◽

Mdr Tb ◽

History Of ◽

Additional Resistance

BACKGROUND:There has been a steady increase in referrals of patients with multidrug-resistant tuberculosis (MDR-TB) who are human immunodeficiency virus (HIV) negative. Between 1986 and 1999, 40 patients were admitted to the authors' institution, eight of whom were admitted between January and June 1999. The management of such individuals is difficult. Although they are a clinically and epidemiologically important group of patients, few reports detail their management.OBJECTIVES:To review the demographics, clinical management and long term outcome of 40 non-HIV-infected individuals with MDR-TB referred to the only specialized TB inpatient service in Ontario.PATIENTS AND METHODS:Clinical hospital records were reviewed.RESULTS:Twenty-one men and 19 women (mean age 41±18 years) were admitted between January 1986 and June 1999 with MDR-TB and negative serology for HIV. Thirty-eight patients (95%) were born outside of Canada. Twenty-six patients (65%) had a history of previous TB. All were symptomatic with productive cough and positive sputum smears for acid-fast bacilli. There was a delay of 4.5 months between the initial diagnosis of TB and the recognition of the presence of MDR-TB. Four patients (10%) had TB resistant to isoniazid and rifampin only. Over 50% of patients had TB with additional resistance to streptomycin, and over 40% had additional resistance to ethambutol. Coexisting resistance was also found in significant numbers for pyrazinamide, ethionamide, para-aminosalicylic acid and cycloserine. Bacteriological conversion was achieved in 34 patients (85%). Six patients underwent surgical resection for localized lung disease. Twenty-four patients completed treatment and have remained free of disease for 33±25 months. All five patients (12%) who died had longstanding disease before their referral. CONCLUSIONS: MDR-TB is most frequently seen among immigrants with a previous history of TB, especially if they come from countries in which TB is highly prevalent. Outcome can be improved by a more timely recognition of MDR-TB.

Download Full-text