Bedaquiline and Repurposed Drugs for Fluoroquinolone-Resistant Multidrug-Resistant Tuberculosis: How Much Better Are They?

Bastard, Mathieu; Guglielmetti, Lorenzo; Huerga, Helena; Hayrapetyan, Armen; Khachatryan, Naira; L, Yegiazaryan; Faqirzai, Jamil; Hovhannisyan, Lana; Varaine, Francis; Hewison, Catherine

doi:10.1164/rccm.201801-0019le

Cited by 19 publications

(29 citation statements)

References 9 publications

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“…When national TB programs and partners used bedaquiline and delamanid alongside repurposed drugs such as linezolid in RR/MDR-TB treatment regimens according to WHO guidance, a high proportion of patients experienced sputum culture conversion by six months. endTB observational study findings are in-line with trials and smaller observational cohorts, which have generally reported six-month conversion outcomes ranging from 70% to 90% (10,11,13,19,37). This is notable because the endTB cohort included patient groups often excluded from trials (i.e., those with: HIV and low CD4; XDR-TB; previous treatment for MDR-TB; uncontrolled DM; coinfection with HIV and hepatitis B or C).…”

Section: Discussionsupporting

confidence: 82%

“…(3)(4)(5)(6)(7) In 2012 and 2013, based on promising Phase II trial data, (8)(9)(10) stringent regulatory authorities approved the first new TB drugs in fifty years, bedaquiline (BDQ) and delamanid (DLM), offering hope for more effective and less toxic MDR-TB treatment. Since then, evidence generated from both randomized trials and observational studies has continued to support a role for these two drugs in MDR-TB treatment; (11)(12)(13)(14)(15)(16)(17)(18)(19)(20) WHO has endorsed their use, gradually broadening the populations in which they might be used. ( TB).…”

Section: Introductionmentioning

confidence: 99%

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Culture Conversion in Patients Treated with Bedaquiline and/or Delamanid. A Prospective Multicountry Study

Franke

Khan

Hewison

et al. 2021

Am J Respir Crit Care Med

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Background Bedaquiline and delamanid offer the possibility of more effective and less toxic multidrug-resistant tuberculosis (MDR-TB) treatment. With this treatment, however, some patients, remain at high risk for an unfavorable treatment outcome. The endTB observational study is the largest multicountry cohort of patients with rifampin-resistant/MDR-TB treated in routine care, according to WHO guidance, with delamanid-and/or bedaquiline-containing regimens. We report frequency of sputum culture conversion within six-months of treatment initiation and risk factors for non-conversion. Methods We included patients with a positive baseline culture who initiated a first endTB regimen prior to April 2018. Two consecutive negative cultures collected > 15 days apart constituted culture conversion. We used generalized mixed models to derive marginal predictions for the probability of culture conversion in key subgroups. Findings 1,109 patients initiated a multidrug treatment containing bedaquiline (63%), delamanid (27%) or both (10%). Of these, 939 (85%) experienced culture conversion within six months. In adjusted analyses, patients with HIV had a lower probability of conversion (0•73 [95% CI: 0•62, 0•84]) than patients without HIV (0•84 [95% CI: 0•79, 0•90]; p=0•03). Patients with both cavitary disease and highly positive sputum smear had a lower probability of conversion (0•68 [95% CI: 0•57, 0•79]) relative to patients without either (0•89; 95% CI: 0•84, 0•95; p=0•0004). Hepatitis C infection, diabetes mellitus/glucose intolerance, and baseline resistance were not associated with conversion.

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Section: Discussionsupporting

confidence: 82%

Section: Introductionmentioning

confidence: 99%

Culture Conversion in Patients Treated with Bedaquiline and/or Delamanid. A Prospective Multicountry Study

Franke

Khan

Hewison

et al. 2021

Am J Respir Crit Care Med

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“…This suggests that even in cases of FQ-R MDR TB including XDR TB, improved treatment outcomes can be achieved if appropriate drug combinations are used. Several recent studies using new drugs or repurposed drugs also yielded results consistent with the present study, in which the treatment success rate of XDR TB was not inferior to that of MDR TB [21, 23–25].…”

Section: Discussionsupporting

confidence: 91%

“…In a recent meta-analysis, the overall pooled successful treatment rate for FQ-S MDR TB was 62%–73% between 2009 and 2016, whereas that of FQ-R MDR TB including XDR TB was 51%–57% during the same period [3]. Recently, however, MDR/XDR TB treatment outcomes have been improved with the use of bedaquiline and delamanid [8, 20, 21], and repurposed drugs such as linezolid, clofazimine, and carbapenems also contributed to the improvement of MDR/XDR TB treatment outcomes [3, 7, 15, 22]. In the current study, FQ-R MDR TB was associated with more severe clinical symptoms such as cavitary lesions, bilateral disease, and higher acid-fast bacillus smear positivity (Table 1).…”

Section: Discussionmentioning

confidence: 99%

Improved Fluoroquinolone-Resistant and Extensively Drug-Resistant Tuberculosis Treatment Outcomes

Lee

Yong

Leem

et al. 2019

Open Forum Infectious Diseases

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Background Treatment outcomes of multidrug-resistant tuberculosis (MDR TB) remain poor, particularly for fluoroquinolone-resistant (FQ-R) MDR TB. The aim of this study was to determine treatment outcomes and factors associated with failure of MDR TB treatment, focusing on FQ resistance. Methods Medical records were retrospectively reviewed of patients diagnosed and treated for MDR TB from January 2005 through December 2017 at Severance Hospital, South Korea. Results Of a total of 129 patients with MDR TB, 90 (69.8%) cases were FQ-sensitive (FQ-S) and 39 (30.2%) were FQ-R. FQ-R MDR TB was associated with more severe clinical symptoms, including cavitary lesions and bilateral disease, and tended to require treatment with a greater number of drugs for a longer period of time than FQ-S MDR TB. Linezolid (51.3% vs 7.8%, P < .001), bedaquiline (20.5% vs 8.9%, P = .083), and delamanid (10.3% vs 5.6%, P = .452) were more frequently used in FQ-R cases. Overall, 95/124 patients (76.6%) had favorable treatment outcomes, and we did not detect a significant difference between FQ-R and FQ-S (FQ-S 65/87, 74.7%, vs FQ-R 30/37, 81.1%; P = .443). Old age, low body mass index, smoking, and malignancy—but not FQ resistance or extensively drug-resistant (XDR) TB—were associated with poor clinical outcomes. Conclusions Overall, 76.6% of MDR TB patients had successful treatment outcomes. Effective drug combinations and appropriate use of new drugs may improve treatment outcomes of FQ-R MDR and XDR TB. Poor clinical outcomes were more related to the patients’ general condition rather than FQ resistance or XDR.

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“…Increasing evidence, primarily from observational cohort studies, suggests that regimens that include new drugs such as bedaquiline (BDQ) and delamanid (DLM) or repurposed drugs such as linezolid and clofazimine can improve DR-TB outcomes, including culture conversion, treatment success and mortality 30–32 . However, some observational cohort data have demonstrated high rates of reversion of culture conversion in patients with FQ-resistant TB, suggesting that longer durations (more than 6 months) of BDQ may be required for patients with more resistant disease 33 .…”

Section: Introductionmentioning

confidence: 99%

Treatment as prevention and other interventions to reduce transmission of multidrug-resistant tuberculosis

Nathavitharana

Lederer

Tierney

et al. 2019

int j tuberc lung dis

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Summary Drug resistant tuberculosis (DR-TB) represents a major programmatic challenge at the national and global level. Only ~30% of patients with multidrug-resistant (MDR) TB were diagnosed and ~25% were initiated on therapy for MDR-TB in 2016. Increasing evidence now points towards primary transmission of DR-TB rather than inadequate treatment as the major driver of the DR-TB epidemic. The cornerstone of DR-TB transmission prevention should be earlier diagnosis and prompt initiation of effective treatment for all patients with DR-TB. Despite the extensive scale up of Xpert MTB/RIF testing, major implementation barriers continue to limit its impact. Although there is longstanding evidence in support of the rapid impact of treatment on patient infectiousness, delays in the initiation of effective DR-TB treatment persist, resulting in ongoing transmission. However, it is also imperative to address the burden of latent DR-TB infection, since it is estimated that many DR-TB patients will become infectious prior to seeking care and encounter various diagnostic delays before treatment. Addressing latent DR-TB primarily consists of identifying, treating and following contacts of patients with MDR-TB, typically through household contact evaluation. Adjunctive measures such as improved ventilation and use of germicidal ultraviolet (GUV) technology can further decrease TB transmission in high-risk congregate settings. Although many gaps remain in our biological understanding of TB transmission, implementation barriers to early diagnosis and rapid initiation of effective DR-TB treatment can and must be overcome if we are to impact DR-TB incidence in the short and long-term.

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Bedaquiline and Repurposed Drugs for Fluoroquinolone-Resistant Multidrug-Resistant Tuberculosis: How Much Better Are They?

Cited by 19 publications

References 9 publications

Culture Conversion in Patients Treated with Bedaquiline and/or Delamanid. A Prospective Multicountry Study

Culture Conversion in Patients Treated with Bedaquiline and/or Delamanid. A Prospective Multicountry Study

Improved Fluoroquinolone-Resistant and Extensively Drug-Resistant Tuberculosis Treatment Outcomes

Treatment as prevention and other interventions to reduce transmission of multidrug-resistant tuberculosis

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