Case Report: Dynamics of Acquired Fluoroquinolone Resistance under Standardized Short-Course Treatment of Multidrug-Resistant Tuberculosis

Ngabonziza, Jean Claude Semuto; Deun, Armand Van; Migambi, Patrick; Niyigena, Esdras Belamo; Dusabe, Théogène; Habimana, Yves Mucyo; Ushizimpumu, Bertin; Mulders, Wim; Decroo, Tom; Affolabi, Dissou; Supply, Philip; Jong, Bouke C. de; Rigouts, Leen

doi:10.4269/ajtmh.20-0201

Cited by 7 publications

(6 citation statements)

References 16 publications

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“…Among the most consequential AEs, nephrotoxicity and ototoxicity associated with injectable drugs (kanamycin, amikacin, or capreomycin) require adequate monitoring to avoid permanent disability or serious consequences for patients. Even though WHO has recommended restricted use of the injectable agents in the most recent guidelines, some individualized regimens in current use may still include these drugs [ 9 , 10 ]. It is essential to understand factors related to the toxicity of injectable agents as it helps build a strategy to minimize the risk.…”

Section: Introductionmentioning

confidence: 99%

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

Nguyen

Thúy

et al. 2021

PLoS ONE

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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.

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Section: Introductionmentioning

confidence: 99%

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

Nguyen

Thúy

et al. 2021

PLoS ONE

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“…Consistent with the routine pDST-based drug-resistance surveillance [45] , as well as the 2015 drug-resistance survey [17] , only two isolates among successfully sequenced RR-TB isolates had a mutation conferring resistance to fluoroquinolones. Overall, the very low rate of fluoroquinolone resistance could partly explain the high treatment success in Rwanda observed with the two WHO-endorsed long and short MDR-TB regimens [17] , [46] .…”

Section: Discussionmentioning

confidence: 55%

Multidrug-resistant tuberculosis control in Rwanda overcomes a successful clone that causes most disease over a quarter century

Ngabonziza

Rigouts

Torrea

et al. 2022

Journal of Clinical Tuberculosis and Other Mycobacterial Diseas

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Summary background Multidrug-resistant (MDR) tuberculosis (TB) poses an important challenge in TB management and control. Rifampicin resistance (RR) is a solid surrogate marker of MDR-TB. We investigated the RR-TB clustering rates, bacterial population dynamics to infer transmission dynamics, and the impact of changes to patient management on these dynamics over 27 years in Rwanda. Methods We analysed whole genome sequences of a longitudinal collection of nationwide RR-TB isolates. The collection covered three important periods: before programmatic management of MDR-TB (PMDT; 1991–2005), the early PMDT phase (2006–2013), in which rifampicin drug-susceptibility testing (DST) was offered to retreatment patients only, and the consolidated phase (2014–2018), in which all bacteriologically confirmed TB patients had rifampicin DST done mostly via Xpert MTB/RIF assay. We constructed clusters based on a 5 SNP cut-off and resistance conferring SNPs. We used Bayesian modelling for dating and population size estimations, TransPhylo to estimate the number of secondary cases infected by each patient, and multivariable logistic regression to assess predictors of being infected by the dominant clone. Results Of 308 baseline RR-TB isolates considered for transmission analysis, the clustering analysis grouped 259 (84.1%) isolates into 13 clusters. Within these clusters, a single dominant clone was discovered containing 213 isolates (82.2% of clustered and 69.1% of all RR-TB), which we named the “Rwanda Rifampicin-Resistant clone” (R3clone). R3clone isolates belonged to Ugandan sub-lineage 4.6.1.2 and its rifampicin and isoniazid resistance were conferred by the Ser450Leu mutation in rpoB and Ser315Thr in katG genes, respectively. All R3clone isolates had Pro481Thr, a putative compensatory mutation in the rpoC gene that likely restored its fitness. The R3clone was estimated to first arise in 1987 and its population size increased exponentially through the 1990s’, reaching maximum size (∼84%) in early 2000 s’, with a declining trend since 2014. Indeed, the highest proportion of R3clone (129/157; 82·2%, 95%CI: 75·3–87·8%) occurred between 2000 and 13, declining to 64·4% (95%CI: 55·1-73·0%) from 2014 onward. We showed that patients with R3clone detected after an unsuccessful category 2 treatment were more likely to generate secondary cases than patients with R3clone detected after an unsuccessful category 1 treatment regimen. Conclusions RR-TB in Rwanda is largely transmitted. Xpert MTB/RIF assay as first diagnostic test avoids unnecessary rounds of rifampicin-based TB treatment, thus preventing ongoing transmission of the dominant R3clone. As PMDT was intensified and all TB patients accessed rifampicin-resistance testing, the nationwide R3clone burden declined. To our knowledge, our findings provide the first evidence supporting the impact of univers...

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“…This might be due to the accumulation of resistance. Although resistance to fluoroquinolone, the second-line core drug, fortunately remains rare in Rwanda, 19 full DST at the start of the second-line treatment as well as a close follow-up, including DST during treatment of late positive cultures, is justified.…”

Section: Discussionmentioning

confidence: 99%

Predictors of Rifampicin-Resistant Tuberculosis Mortality among HIV-Coinfected Patients in Rwanda

Habimana

Ngabonziza

Migambi

et al. 2021

The American Journal of Tropical Medicine and Hygiene

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Tuberculosis (TB), including multidrug-resistant (MDR; i.e., resistant to at least rifampicin and isoniazid)/rifampicin-resistant (MDR/RR) TB, is the most important opportunistic infection among people living with HIV (PLHIV). In 2005, Rwanda launched the programmatic management of MDR/RR-TB. The shorter MDR/RR-TB treatment regimen (STR) has been implemented since 2014. We analyzed predictors of MDR/RR-TB mortality, including the effect of using the STR overall and among PLHIV. This retrospective study included data from patients diagnosed with RR-TB in Rwanda between July 2005 and December 2018. Multivariable logistic regression was used to assess predictors of mortality. Of 898 registered MDR/RR-TB patients, 861 (95.9%) were included in this analysis, of whom 360 (41.8%) were HIV coinfected. Overall, 86 (10%) patients died during MDR/RR-TB treatment. Mortality was higher among HIV-coinfected compared with HIV-negative TB patients (13.3% versus 7.6%). Among HIV-coinfected patients, patients aged ≥ 55 years (adjusted odds ratio = 5.89) and those with CD4 count ≤ 100 cells/mm3 (adjusted odds ratio = 3.77) had a higher likelihood of dying. Using either the standardized longer MDR/RR-TB treatment regimen or the STR was not correlated with mortality overall or among PLHIV. The STR was as effective as the long MDR/RR-TB regimen. In conclusion, older age and advanced HIV disease were strong predictors of MDR/RR-TB mortality. Therefore, special care for elderly and HIV-coinfected patients with ≤ 100 CD4 cells/mL might further reduce MDR/RR-TB mortality.

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Case Report: Dynamics of Acquired Fluoroquinolone Resistance under Standardized Short-Course Treatment of Multidrug-Resistant Tuberculosis

Cited by 7 publications

References 16 publications

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

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

Multidrug-resistant tuberculosis control in Rwanda overcomes a successful clone that causes most disease over a quarter century

Predictors of Rifampicin-Resistant Tuberculosis Mortality among HIV-Coinfected Patients in Rwanda

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