Extensive Drug Resistance Acquired During Treatment of Multidrug-Resistant Tuberculosis

Cegielski, J. Peter; Dalton, Tracy; Yagui, Martín; Wattanaamornkiet, Wanpen; Volchenkov, Grigory; Via, Laura E.; Walt, Martie van der; Tupasi, Thelma E.; Smith, Sarah E.; Odendaal, Ronel; Leimane, Vaira; Kvasnovsky, Charlotte; Кузнецова, Т. А.; Kurbatova, Ekaterina V.; Kummik, Tiina; Kukša, Līga; Kliiman, Kai; Kir'yanova, E. V.; Kim, Hee Jin; Kim, Chang-ki; Kazennyy, Boris Y.; Jou, Ruwen; Huang, Wei‐Lun; Ershova, Julia; Erokhin, V V; Diem, Lois; Contreras, Carmen; Cho, Sang Nae; Черноусова, Л. Н.; Chen, Michael P.; Caoili, Janice Campos; Bayona, Jaime; Akksilp, Somsak; Calahuanca, Gloria Yale; Wolfgang, Melanie; Viiklepp, Piret; Vasilieva, I. A.; Taylor, Andrew; Tan, K K; Suarez, Carmen; Sture, Ingrida; Somova, Tatiana R.; Смирнова, Т. Г.; Sigman, Erika; Šķenders, Ģirts; Sitti, Wanlaya; Shamputa, Isdore Chola; Riekstiņa, Vija; Pua, Kristine Rose; Therese, M.; Pérez, Cristina Carbajales; Park, Seung-Kyu; Norvaisha, Inga; Nemtsova, E.; Min, Seonyeong; Metchock, Beverly; Levina, Klavdia; Lei, Yung-Chao; Lee, Jong-Seok; Larionova, Elena; Lancaster, Joey; Jeon, Doosoo; Jave, Oswaldo; Khorosheva, Tatiana; Hwang, Sung-Kyun; Huang, Angela; Gler, Ma Tarcela; Dravniece, Gunta; Eum, Seok-Yong; Demikhova, Olga V.; Degtyareva, I. I.; Danilovitš, Manfred; Cirula, Anda; Cho, Eunjin; Cai, Ying; Brand, Jeanette; Bonilla, César; Barry, Clifton E.; Asencios, Luis; Andreevskaya, Sofya; Akksilp, Rattanawadee

doi:10.1093/cid/ciu572

Cited by 133 publications

(119 citation statements)

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“…Even if we recalculated target attainment using a higher free fraction of 0.85, only 8 patients using an MIC of 1 mg/liter-and no patients using an MIC of 2 mg/liter-reached the therapeutic target. In both situations, this lack of drug exposure may contribute to the risk of acquired resistance, as shown by Cegielski et al (20); often low values of C max preceded acquired drug resistance. However, these data need to be interpreted relative to MIC values.…”

Section: Discussionmentioning

confidence: 91%

“…Despite the general preference for MFX to LFX, earlier studies showed no difference in sputum culture conversion after 3 months of treatment (18,19). Because LFX has no effect on the QT period, it may be safer than MFX in combinations with newer anti-TB drugs such as bedaquiline and delamanid (20). Furthermore, recent studies showed the emergence of drug resistance to FQs during MDR-TB treatment (20).…”

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confidence: 99%

“…Because LFX has no effect on the QT period, it may be safer than MFX in combinations with newer anti-TB drugs such as bedaquiline and delamanid (20). Furthermore, recent studies showed the emergence of drug resistance to FQs during MDR-TB treatment (20). It was suggested that this could be explained by low FQ drug exposure (21).…”

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confidence: 99%

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Pharmacokinetics of Levofloxacin in Multidrug- and Extensively Drug-Resistant Tuberculosis Patients

Boveneind-Vrubleuskaya

Seuruk

Hateren

et al. 2017

Antimicrob Agents Chemother

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Pharmacodynamics are especially important in the treatment of multidrug-and extensively drug-resistant tuberculosis (M/XDR-TB). The free area under the concentration time curve in relation to MIC (fAUC/MIC) is the most relevant pharmacokinetic (PK)-pharmacodynamic (PD) parameter for predicting the efficacy of levofloxacin (LFX). The objective of our study was to assess LFX PK variability in M/XDR-TB patients and its potential consequence for fAUC/MIC ratios. Patients with pulmonary M/XDR-TB received LFX as part of the treatment regimen at a dose of 15 mg/kg administered once daily. Blood samples obtained at steady state before and 1, 2, 3, 4, 7, and 12 h after drug administration were measured by validated liquid chromatography-tandem mass spectrometry. The MIC values of LFX were determined by the agar dilution method on Middlebrook 7H10 and the MGIT960 system. Twenty patients with a mean age of 31 years (interquartile range [IQR] ϭ 27 to 35 years) were enrolled in this study. The median AUC 0 -24 was 98.8 mg/h/liter (IQR ϭ 84.8 to 159.6 mg/h/liter). The MIC median value for LFX was 0.5 mg/liter with a range of 0.25 to 2.0 mg/liter, and the median fAUC 0 -24 /MIC ratio was 109.5 (IQR ϭ 48.5 to 399.4). In 4 of the 20 patients, the value was below the target value of Ն100. When MICs of 0.25, 0.5, 1.0, and 2.0 mg/liter were applicable, 19, 18, 3, and no patients, respectively, had an fAUC/MIC ratio that exceeded 100. We observed a large variability in AUC. An fAUC 0 -24 /MIC of Ն100 was only observed when the MIC values for LFX were 0.25 to 0.5 mg/liter. Dosages exceeding 15 mg/kg should be considered for target attainment if exposures are assumed to be safe. (This study has been registered at ClinicalTrials.gov under registration no. NCT02169141.)

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Section: Discussionmentioning

confidence: 91%

mentioning

confidence: 99%

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Pharmacokinetics of Levofloxacin in Multidrug- and Extensively Drug-Resistant Tuberculosis Patients

Boveneind-Vrubleuskaya

Seuruk

Hateren

et al. 2017

Antimicrob Agents Chemother

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“…An important issue is the emergence of bacillary resistance to new drugs, as has happened to streptomycin, isoniazid, and rifampicin after their introduction as a result of multiple avoidable factors [30,31]. It is thus imperative that novel drugs be used in adequate dosages and combinations under an optimal healthcare infrastructure [32] to forestall the occurrence of drug resistance.…”

Section: Introductionmentioning

confidence: 99%

Novel drugs against tuberculosis: a clinician's perspective

et al. 2014

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The United Nations Millennium Development Goal of reversing the global spread of tuberculosis by 2015 has been offset by the rampant re-emergence of drug-resistant tuberculosis, in particular fluoroquinolone-resistant multidrug-resistant and extensively drug-resistant tuberculosis. After decades of quiescence in the development of antituberculosis medications, bedaquiline and delamanid have been conditionally approved for the treatment of drug-resistant tuberculosis, while several other novel compounds (AZD5847, PA-824, SQ109 and sutezolid) have been evaluated in phase II clinical trials. Before novel drugs can find their place in the battle against drug-resistant tuberculosis, linezolid has been compassionately used with success in the treatment of fluoroquinolone-resistant multidrug-resistant tuberculosis. This review largely discusses six novel drugs that have been evaluated in phase II and III clinical trials, with focus on the clinical evidence for efficacy and safety, potential drug interactions, and prospect for using multiple novel drugs in new regimens. @ERSpublications A review of the efficacy, safety, and potential of new drugs to improve TB therapy from the perspective of clinicians

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“…Treatment outcomes are poor for MDR-TB, with <50% treatment success globally and in both settings included in our study [3,4]; outcomes are even worse for patients infected with strains with additional second-line resistance [5]. Persistent use of standardised regimens that are potentially inadequate in cases with known SLD resistance, or where standardised treatment has already failed, is likely to contribute to the emerging extensively drug-resistant tuberculosis (XDR-TB) epidemic due to further acquisition of SLD resistance through selective drug pressure [6], particularly in high-burden settings. This defines the need for strengthened treatment regimens including new TB drugs, both to improve individual patient outcomes and to prevent undertreatment on a programmatic level that drives further resistance.…”

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confidence: 99%

Linezolid in drug-resistant tuberculosis: haste makes waste

Hughes

Isaakidis²,

Andries³

et al. 2015

Eur Respir J

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(300-600 mg per day). However, it recommends that the safety profile of linezolid does not warrant its use in cases where there are other, safer, alternatives [7]. Furthermore, use of linezolid in improper dosage and duration have been associated with increased risk of acquired drug resistance and adverse effects/outcome may be more in those patients of XDR-TB infected with linezolid resistant strains when treated with regimens containing linezolid [8].We have already lost the two most important first-line drugs, i.e. rifampicin and isoniazid to MDR-TB, and the two most important second-line drugs, i.e. fluoroquinolone and injectable anti-TB drugs, to XDR-TB and now it would not be wise to lose one of the key drugs in the treatment of XDR-TB, i.e. linezolid to the imminent "resistance beyond XDR-TB" [9]. Several clinicians refer to this dreaded condition as total drug resistance, although this terminology has not yet been recognised by WHO. Hence, at this juncture, it would be sensible to restrict the use of linezolid in XDR-TB and complicated drugresistant TB cases only, as per the WHO guidelines, rather than in all cases of drug-resistant TB. It is well known that treatment outcomes, even under optimal conditions, are relatively poor for MDR-TB and are even worse for XDR-TB [10]. Treatment options for these XDR-TB patients are extremely limited and often rely on a set of drugs with poorly established efficacy and severe adverse events profile. Therefore, the drugs in the armamentarium for XDR-TB should be used judiciously and with utmost care, lest we run out of ammunition in the battle field of XDR-TB.@ERSpublications The use of linezolid should be preserved for XDR-TB and complicated drug-resistant-TB only

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Extensive Drug Resistance Acquired During Treatment of Multidrug-Resistant Tuberculosis

Abstract: Treatment of MDR tuberculosis involves substantial risk of acquired resistance to SLDs, increasing as baseline drug resistance increases. The risk was significantly lower in programs documented by the GLC to meet specific standards.

Cited by 133 publications

References 11 publications

Pharmacokinetics of Levofloxacin in Multidrug- and Extensively Drug-Resistant Tuberculosis Patients

Pharmacokinetics of Levofloxacin in Multidrug- and Extensively Drug-Resistant Tuberculosis Patients

Novel drugs against tuberculosis: a clinician's perspective

Linezolid in drug-resistant tuberculosis: haste makes waste

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