Comparison of
            <i>In Vitro</i>
            Activity and MIC Distributions between the Novel Oxazolidinone Delpazolid and Linezolid against Multidrug-Resistant and Extensively Drug-Resistant Mycobacterium tuberculosis in China

Zong, Zhaojing; Wei, Jing; Shi, Jin; Wen, Shuan; Zhang, Tingting; Huo, Fengmin; Shang, Yuanyuan; Liang, Qian; Huang, Hairong; Pang, Yu

doi:10.1128/aac.00165-18

Cited by 66 publications

(47 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Limited evidence suggests that population-level resistance to linezolid may be increasing in TB programmes 8 . Linezolid shares key binding sites and displays cross-resistance with other oxazolidinones, including promising new agents in clinical development, such as sutezolid 9 and delpazolid 10 . Mutations in genes encoding the 23S rRNA ( rrl ) linezolid peptidyl transferase centre (PTC) binding site and the L3 protein ( rplC ), which extends into the binding site, have been identified as the dominant molecular mechanisms underlying linezolid resistance from in vitro and clinical studies 4 , 9–19 .…”

Section: Introductionmentioning

confidence: 99%

Linezolid resistance in patients with drug-resistant TB and treatment failure in South Africa

Wasserman

Louw

Ramangoaela

et al. 2019

Journal of Antimicrobial Chemotherapy

View full text Add to dashboard Cite

Objectives Limited data exist on clinical associations and genotypic correlates of linezolid resistance in Mycobacterium tuberculosis. We aimed to describe mutations and clinical factors associated with phenotypic linezolid resistance from patients with drug-resistant TB at two public sector facilities in South Africa. Methods Adults and adolescents with treatment failure (culture positivity ≥4 months) on a linezolid-containing regimen were retrospectively identified. Phenotypic resistance, as defined by a linezolid MIC >1 mg/L, was assessed for retrieved isolates using broth microdilution. Targeted sequencing of rrl and rplC was performed, irrespective of growth on subculture. Results Thirty-nine patients with linezolid-based treatment failure were identified, 13 (33%) of whom had phenotypic or genotypic linezolid resistance after a median duration of 22 months (range = 7–32) of linezolid therapy. Paired MIC testing and genotyping was performed on 55 unique isolates. All isolates with phenotypic resistance (n = 16) were associated with known resistance mutations, most frequently due to the T460C substitution in rplC (n = 10); rrl mutations included G2814T, G2270C/T and A2810C. No mutations were detected in isolates with MICs at or below the critical concentration. Conclusions Linezolid resistance occurred in a third of patients with drug-resistant TB and treatment failure. Resistance occurred late and was predicted by a limited number of mutations in rrl and rplC. Screening for genotypic resistance should be considered for patients with a positive culture after 4 months of linezolid therapy in order to optimize treatment and avoid the toxicity of ineffective linezolid therapy.

show abstract

Section: Introductionmentioning

confidence: 99%

Linezolid resistance in patients with drug-resistant TB and treatment failure in South Africa

Wasserman

Louw

Ramangoaela

et al. 2019

Journal of Antimicrobial Chemotherapy

View full text Add to dashboard Cite

show abstract

“…Due to funding and market incentive mechanisms promoting and supporting anti-TB drug development, several new promising anti-TB candidates for the treatment of drug-resistant TB are in clinical development. Apart from the clinical evaluation of novel analogues of validated anti-TB drug classes, including the riminophenazine analogue TBI-166 [140] as a less toxic alternative of the second-line anti-TB agent clofazimine and the oxazolidinone analogues TBI-223 [141], contezolid [142,143,144], sutezolid [145,146] and delpazolid [147,148] as more effective and safer linezolid alternatives, novel chemical entities are assessed as well. As these candidates interact with novel mycobacterial targets, they may provide an alternative treatment option for drug-resistant TB infections and could counteract the emergence of drug resistance when given in combination with existing anti-TB drugs.…”

Section: Discussionmentioning

confidence: 99%

Opportunities for Overcoming Mycobacterium tuberculosis Drug Resistance: Emerging Mycobacterial Targets and Host-Directed Therapy

Torfs

Piller

Cos

et al. 2019

IJMS

View full text Add to dashboard Cite

The ever-increasing incidence of drug-resistant Mycobacterium tuberculosis infections has invigorated the focus on the discovery and development of novel treatment options. The discovery and investigation of essential mycobacterial targets is of utmost importance. In addition to the discovery of novel targets, focusing on non-lethal pathways and the use of host-directed therapies has gained interest. These adjunctive treatment options could not only lead to increased antibiotic susceptibility of Mycobacterium tuberculosis, but also have the potential to avoid the emergence of drug resistance. Host-directed therapies, on the other hand, can also reduce the associated lung pathology and improve disease outcome. This review will provide an outline of recent opportunities.

show abstract

“…As a novel oxazolidinone prodrug, TZD exhibited greater potency than LZD against M. tuberculosis (6, 27) as well as against NTM(28, 29). Limited studies or no study has been performed to evaluate the efficacy of SZD and DZD against NTM species(28), whereas only a few studies provided preliminarily assessment of their potential usage in TB(14, 30, 31). In this study, we evaluated the efficacies of four oxazolidinones against the reference and clinical isolates of RGM to gain insights on their potential use for specific RGM species.…”

Section: Discussionmentioning

confidence: 99%

In Vitroefficacy comparison of linezolid, tedizolid, sutezolid and delpazolid against rapid growing Mycobacteria isolated in Beijing, China

Wen

Gao

Zhao

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

The natural resistance of rapid growth Mycobacterium (RGM) against multiple antibiotics renders the treatment of caused infections less successful and time consuming. Therefore, new effective agents are urgently needed. The aim of this study was to evaluate the in vitro susceptibility of 115 isolates, constituting different RGM species, against four oxazolidinones i.e. delpazolid, sutezolid, tedizolid and linezolid. Additionally, 32 reference strains of different RGM species were also tested. The four oxazolidinones exhibited potent in vitro activity against the recruited RGM reference strains, 24 out of 32 RGM species had MICs ≤ 8 μg/mL against all four oxazolidinones whereas tedizolid and delpazolid generally presented lower MICs than linezolid or sutezolid. Tedizolid showed the strongest activity against clinical isolates of M. abscessus with MIC50=1μg/mL and MIC90=2μg/mL. MIC values for tedizolid were usually 4- to 8-fold less than the MICs of linezolid for M. abscessus subsp. abscessus. The MIC distributions of sutezolid and linezolid were similar, while delpazolid showed 2-fold lower MIC as compared with linezolid. Linezolid was not active against most of the tested M. fortuitum isolates, 22 out of the 25 M. fortuitum were resistant against linezolid. However, delpazolid exhibited better antimicrobial activity against these isolates with 4-fold lower MIC values, in contrast with linezolid. In addition, the protein alignment of RplC and RplD and structure based analysis showed that there may be no correlation between oxazolidinones resistance and mutations in rplC, rplD and 23 srRNAgenes in tested RGM. This study showed tedizolid harbors the strongest inhibitory activity against M. abscessus in vitro, while delpazolid presented the best activity against M. fortuitum, which provided important insights on the potential clinical application of oxazolidinones to treat RGM infections.

show abstract

Comparison of In Vitro Activity and MIC Distributions between the Novel Oxazolidinone Delpazolid and Linezolid against Multidrug-Resistant and Extensively Drug-Resistant Mycobacterium tuberculosis in China

Cited by 66 publications

References 20 publications

Linezolid resistance in patients with drug-resistant TB and treatment failure in South Africa

Linezolid resistance in patients with drug-resistant TB and treatment failure in South Africa

Opportunities for Overcoming Mycobacterium tuberculosis Drug Resistance: Emerging Mycobacterial Targets and Host-Directed Therapy

In Vitroefficacy comparison of linezolid, tedizolid, sutezolid and delpazolid against rapid growing Mycobacteria isolated in Beijing, China

Contact Info

Product

Resources

About