In Vitro Activity of Linezolid against Clinical Isolates of Mycobacterium tuberculosis, including Multidrug-Resistant and Extensively Drug-Resistant Strains from Beijing, China

Yang, Caie; Hong, Lei; Wang, Di; Meng, Xia; He, Jian‐Qing; Tong, Aihua; Zhu, Li; Jiang, Ying; Ming, Dong

doi:10.7883/yoken.65.240

Cited by 20 publications

(7 citation statements)

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“…The MIC values of LZD alone for M. tuberculosis, observed in this study (0.125e2.5 mg/ml), were similar to those observed in studies carried out by Guna et al [8] (0.125e4.0 mg/ml), Ermertcan et al [19] (0.6e1.0 mg/ml), Alffenaar et al [20] ( 0.25e1.0 mg/ml), Alcala et al [6] (1.0e2.0 mg/ml) and Yang et al [21] (0.125e0.5 mg/ml),…”

Section: Discussionsupporting

confidence: 91%

Activity of rifampicin and linezolid combination in Mycobacterium tuberculosis

et al. 2017

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By Time Kill Curve Assay, we could observe in M. tuberculosis HRv and susceptible isolates, that LZD alone, at sub inhibitory concentration, has poor effect on the bacillus death. In some cases, the bacillus growth stayed constant while in others showed regrowth at the eighth day of drug exposure. RIF alone exhibits potent concentration-dependent bactericidal activity, and was strongly dependent by the drug exposure time. The RIF/LZD combination accomplished a bacteriostatic effect in the reference strain and susceptible isolates. For the RIF resistant isolates, the RIF/LZD combination did not enhance the effect in killing bacillus. In this sense, additional, in vitro and in vivo studies are needed to evaluate the effect of RIF/LZD combination in order to better understand the adjunctive action of LZD in the treatment of TB and prevent the emergence of mutants with resistance to the available anti-TB drugs.

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Section: Discussionsupporting

confidence: 91%

Activity of rifampicin and linezolid combination in Mycobacterium tuberculosis

et al. 2017

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“…The target attainment probability, which is how well a dose of 150 mg, 300 mg, 600 mg, or 1,200 mg would achieve the EC 80 in the lung of tuberculosis patients at each MIC, was then calculated. We utilized three different MIC distributions from Spain, China, and Germany (466 clinical isolates) (41–43). The cumulative fraction of response (CFR) for each dose was then summated over the MIC distribution.…”

Section: Methodsmentioning

confidence: 99%

Linezolid Dose That Maximizes Sterilizing Effect While Minimizing Toxicity and Resistance Emergence for Tuberculosis

Srivastava

Magombedze

Koeuth

et al. 2017

Antimicrob Agents Chemother

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Linezolid has an excellent sterilizing effect in tuberculosis patients but high adverse event rates. The dose that would maximize efficacy and minimize toxicity is unknown. We performed linezolid dose-effect and dose-scheduling studies in the hollow fiber system model of tuberculosis (HFS-TB) for sterilizing effect. HFS-TB units were treated with several doses to mimic human-like linezolid intrapulmonary pharmacokinetics and repetitively sampled for drug concentration, total bacterial burden, linezolid-resistant subpopulations, and RNA sequencing over 2 months. Linezolid-resistant isolates underwent whole-genome sequencing. The expression of genes encoding efflux pumps in the first 1 to 2 weeks revealed the same exposure-response patterns as the linezolid-resistant subpopulation. Linezolid-resistant isolates from the 2nd month of therapy revealed mutations in several efflux pump/transporter genes and a LuxR-family transcriptional regulator. Linezolid sterilizing effect was linked to the ratio of unbound 0- to 24-h area under the concentration-time curve (AUC0–24) to MIC. Optimal microbial kill was achieved at an AUC0–24/MIC ratio of 119. The optimal sterilizing effect dose for clinical use was identified using Monte Carlo simulations. Clinical doses of 300 and 600 mg/day (or double the dose every other day) achieved this target in 87% and >99% of 10,000 patients, respectively. The susceptibility breakpoint identified was 2 mg/liter. The simulations identified that a 300-mg/day dose did not achieve AUC0–24s associated with linezolid toxicity, while 600 mg/day achieved those AUC0–24s in <20% of subjects. The linezolid dose of 300 mg/day performed well and should be compared to 600 mg/day or 1,200 mg every other day in clinical trials.

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“…Linezolid an Oxazolidinone and a relatively newer class of antibiotic has demonstrated potency against drug-resistant M. tuberculosis in a number of in vitro studies [ 16 – 18 ]. Since 2006, the WHO has recommended the use of linezolid in the treatment of MDR/XDR-TB with the drug now being included in many TB programmes across the world [ 19 , 20 ].…”

Section: Introductionmentioning

confidence: 99%

Efficacy and safety profile of linezolid in the treatment of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis: a systematic review and meta-analysis

Agyeman

Ofori‐Asenso

2016

Ann Clin Microbiol Antimicrob

102

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BackgroundTreatment options for drug-resistant tuberculosis are still limited. Linezolid has been recommended for treatment of patients with multidrug-resistant (MDR) or extensively-drug-resistant (XDR) tuberculosis, although uncertainties remain regarding its safety and tolerability in these circumstances.ObjectiveTo systematically evaluate the existing evidence regarding the efficacy and tolerability of linezolid in the treatment of MDR or XDR tuberculosis.MethodsWe conducted a systematic review and meta-analysis in accordance with the PRISMA guidelines. Searches were conducted in PubMed, Web of Science and EMBASE followed by direct search of abstracts in the International Journal of Tuberculosis and Lung Disease to retrieve primary studies published between January 2000 and January 2016 assessing linezolid efficacy and safety in the treatment of drug-resistant TB. We evaluated the occurrence of outcomes including culture conversion, treatment success and incidence of adverse events such as myelosuppression and neuropathy.ResultsTwenty-three (23) studies conducted in fourteen (14) countries and involving 507 patients were retrieved. Only 1 randomized controlled trial was identified and none of the identified studies involved participants from Africa. The pooled proportion for treatment success was 77.36 % (95 % CI = 71.38–82.83 %, I2 = 37.6 %) with culture conversion rate determined as 88.45 % (95 % CI = 83.82–92.38 %, I2 = 45.4 %). There was no strong evidence for both culture conversion (p = 0.0948) and treatment success (p = 0.0695) between linezolid daily doses ≤ 600 and > 600 mg. Only myelosuppression showed a strong statistical significance (p < 0.0001) between dose comparisons. The incidence of neuropathy and other adverse events leading to permanent discontinuation of linezolid also showed no significance upon dose comparisons (p = 0.3213, p = 0.9050 respectively).ConclusionAvailable evidence presents Linezolid as a viable option in the treatment of MDR/XDR TB although patients ought to be monitored closely for the incidence of major adverse events such as myelosuppression and neuropathy. Additionally, highly powered randomized controlled trials including participants from endemic regions are urgently needed to better inform the magnitude and significance of Linezolid treatment effect in MDR and XDR TB patients.Electronic supplementary materialThe online version of this article (doi:10.1186/s12941-016-0156-y) contains supplementary material, which is available to authorized users.

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In Vitro Activity of Linezolid against Clinical Isolates of Mycobacterium tuberculosis, including Multidrug-Resistant and Extensively Drug-Resistant Strains from Beijing, China

Cited by 20 publications

References 9 publications

Activity of rifampicin and linezolid combination in Mycobacterium tuberculosis

Activity of rifampicin and linezolid combination in Mycobacterium tuberculosis

Linezolid Dose That Maximizes Sterilizing Effect While Minimizing Toxicity and Resistance Emergence for Tuberculosis

Efficacy and safety profile of linezolid in the treatment of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis: a systematic review and meta-analysis

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