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• W3126681567 abstract "FOR RELATED ARTICLE, SEE PAGE 517In this issue of CHEST, Kwak et al1Kwak N. Whang J. Yang J.S. et al.Minimal inhibitory concentration of clofazimine among clinical isolates of nontuberculous mycobacteria and its impact on treatment outcome.Chest. 2021; 159: 517-523Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar report a novel effort to correlate clofazimine in vitro susceptibility results for Mycobacterium avium complex (MAC) and M abscessus with clinical outcomes using clofazimine-containing treatment regimens for these organisms. Their study highlights the many difficulties confronting such an evaluation while emphasizing the importance of systematically studying this question going forward. FOR RELATED ARTICLE, SEE PAGE 517 In vitro drug susceptibility testing (DST) that involves antimicrobials that are used for the treatment of nontuberculous mycobacteria (NTM) in general and MAC specifically is controversial, poorly understood, and frequently misapplied. Confusion and frustration with NTM DST is rooted in the inability to apply minimum inhibitory concentration (MIC) principles and MIC “susceptibility” breakpoints applicable for M TB to NTM. DST is appropriate if (a) there is an infection/disease that needs antimicrobial therapy, (b) effective antimicrobial drugs are available to the patient, (c) there is a known suitable platform to perform the test for the relevant drugs, (d) the activity of the drugs in vitro is related to their effect in vivo, and (e) the in vitro activities of the drugs vary (eg, resistance can emerge).2van Ingen J. Drug susceptibility testing of non-tuberculous mycobacteria.in: Griffith DE, editor. Nontuberculous Mycobacterial Disease (A comprehensive approach to diagnosis and management). Humana Press, New York2019: 61-88Crossref Google Scholar The Clinical and Laboratory Standards Institute in vitro DST recommendations regarding macrolides and amikacin illustrate these points.3Woods G.L. Brown-Elliott B.A. Conville P.S. et al.Susceptibility testing of mycobacteria, nocardiae, and other aerobic actinomycetes [Internet].2nd ed. Clinical and Laboratory Standards Institute, Wayne (PA)2011Google Scholar Both are associated with clinical efficacy, have a narrow range of MIC values for untreated (wild-type) isolates, have MIC cutpoints that predict treatment outcomes, and have clinically meaningful associations between MIC and the effect of specific mutations on clinical response. No other MAC antimicrobial satisfies all of these criteria. There are no established MIC breakpoints differentiating “susceptible” from “resistant” isolates with MAC for rifamycin, ethambutol, and streptomycin.3Woods G.L. Brown-Elliott B.A. Conville P.S. et al.Susceptibility testing of mycobacteria, nocardiae, and other aerobic actinomycetes [Internet].2nd ed. Clinical and Laboratory Standards Institute, Wayne (PA)2011Google Scholar For these three anti-TB drugs with MAC, (a) MICs are generally high, which is consistent with in vitro resistance as defined by M TB MIC breakpoints; (b) there is a broad MIC range that demonstrates no clear delineation between untreated (wild-type) and treated isolates, and (c) there is an absence of critical mutations associated with in vitro “resistance” and poor clinical response. Similarly, fluoroquinolones lack an established correlation between MICs and clinical response. In patients with treatment refractory MAC who were given moxifloxacin, the treatment success rates did not differ between patients whose isolates were moxifloxacin “resistant” as defined by M TB MIC breakpoints and those whose isolates were “susceptible.”4Koh W.J. Hong G. Kim S.Y. et al.Treatment of refractory Mycobacterium avium complex lung disease with a moxifloxacin-containing regimen.Antimicrob Agents Chemother. 2013; 57: 2281-2285Crossref PubMed Scopus (58) Google Scholar Resistance-associated mutations in gyrA or gyrB were not found in MAC or M abscessus clinical isolates, including moxifloxacin-“resistant” isolates.5Kim S.Y. Jhun B.W. Moon S.M. et al.Mutations in gyrA and gyrB in moxifloxacin-resistant Mycobacterium avium complex and Mycobacterium abscessus complex clinical isolates.Antimicrob Agents Chemother. 2018; 62 (e00527-18)Crossref Scopus (11) Google Scholar The range of linezolid MICs for MAC are similar to the rifamycin, ethambutol, and moxifloxacin and are unlikely to be associated with clinical efficacy at tolerable doses.6Brown-Elliott B.A. Wallace Jr., R.J. In vitro susceptibility testing of tedizolid against nontuberculous mycobacteria.J Clin Microbiol. 2017; 55: 1747-1754Crossref PubMed Scopus (49) Google Scholar Tedizolid MICs for MAC and M abscessus subsp abscessus isolates are 4-fold lower than linezolid, which might result in improved clinical response compared with linezolid, but little outcomes data have been published for either agent. In a recent report, 90% of MAC isolates had bedaquiline MICs of ≤0.008 μg/mL, and 99% of isolates had MICs of ≤0.015 μg/mL.7Brown-Elliott B.A. Philley J.V. Griffith D.E. Thakkar F. Wallace Jr., R.J. In vitro susceptibility testing of bedaquiline against Mycobacterium avium complex.Antimicrob Agents Chemother. 2017; 61 (e01798-16)Crossref Scopus (35) Google Scholar The bedaquiline MIC50 value for M abscessus subsp abscessus was 0.12 μg/mL.8Brown-Elliott B.A. Wallace Jr., R.J. In vitro susceptibility testing of bedaquiline against Mycobacterium abscessus complex.Antimicrob Agents Chemother. 2019; 63 (e01919-18)Crossref PubMed Scopus (22) Google Scholar In spite of low bedaquiline MICs, preliminary results of bedaquiline-containing regimen for a small number of patients with refractory MAC and patients with M abscessus lung disease show marginal efficacy.9Philley J.V. Wallace Jr., R.J. Benwill J.L. et al.Preliminary results of bedaquiline as salvage therapy for patients with nontuberculous mycobacterial lung disease.Chest. 2015; 148: 499-506Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar Bedaquiline also illustrates the complexity of applying the DST principles described earlier. MAC isolates from patients who received bedaquiline and had microbiologic relapse revealed the appearance of mutations in the locus mmpT5, which are associated with up-regulation of the mmpL5 efflux pump gene, which suggests that overexpression of the mmpL5 efflux pump is responsible for the observed resistance.10Alexander D.C. Vasireddy R. Vasireddy S. Emergence of mmpT5 variants during bedaquiline treatment of Mycobacterium intracellulare lung disease.J Clin Microbiol. 2017; 55: 574-584Crossref PubMed Scopus (52) Google Scholar The mmpT5 mutations were associated with modest 2- to 8-fold increases in bedaquiline MICs. Therefore, bedaquiline has (a) very low NTM MICs, (b) a mutation associated with microbiologic failure, (c) MICs from untreated (wild-type) MAC isolates that differ from treated (relapse) MAC isolates (even though MICs minimally change), but (d) marginal clinical effectiveness, Clearly, the bar is very high for establishing a link between the MIC of an NTM antibiotic and clinical response to that antibiotic. Clofazimine is a riminophenazine antibiotic likely with multiple mechanisms of antimicrobial activity that include the generation of antimicrobial reactive oxygen species and cell membrane disruption.11Cholo M.C. Mothiba M.T. Fourie B. Anderson R. Mechanisms of action and therapeutic efficacies of the lipophilic antimycobacterial agents clofazimine and bedaquiline.J Antimicrob Chemother. 2017; 72: 338-353Crossref PubMed Scopus (73) Google Scholar Clofazimine also shares a mechanism of MAC cross-resistance with bedaquiline, regulatory gene mutations resulting in up-regulation of the mmpL5 efflux pump gene.11Cholo M.C. Mothiba M.T. Fourie B. Anderson R. Mechanisms of action and therapeutic efficacies of the lipophilic antimycobacterial agents clofazimine and bedaquiline.J Antimicrob Chemother. 2017; 72: 338-353Crossref PubMed Scopus (73) Google Scholar It is not clear that M abscessus has the same mechanism of clofazimine resistance. Kwak et al1Kwak N. Whang J. Yang J.S. et al.Minimal inhibitory concentration of clofazimine among clinical isolates of nontuberculous mycobacteria and its impact on treatment outcome.Chest. 2021; 159: 517-523Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar report in vitro clofazimine MICs for 133 MAC strains and 40 M abscessus strains. Clofazimine MICs for MAC ranged from 0.031 to 16 μg/mL and for M abscessus from 0.031 to 16 μg/mL. Eight of 20 patients who were treated with clofazimine-containing regimens converted sputum to negative including all five patients (two with MAC, three with M abscessus) with clofazimine MICs ≤0.25 μg/mL. Clofazimine remains an enigmatic component of the NTM treatment armamentarium with persistent questions about its clinical efficacy. Kwak et al1Kwak N. Whang J. Yang J.S. et al.Minimal inhibitory concentration of clofazimine among clinical isolates of nontuberculous mycobacteria and its impact on treatment outcome.Chest. 2021; 159: 517-523Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar adopt an innovative approach in an attempt to clarify the contribution of clofazimine in multidrug regimens for the treatment of MAC and M abscussus lung disease. In that regard, their data suggest that a clofazimine MIC ≤0.25 μg/mL for MAC or M abscessus is predictive of a favorable treatment response. They also report a surprisingly wide range of clofazimine MICs for MAC and M abscessus isolates. Although this study presents some provocative data, the small retrospective and observational nature of the study makes it difficult to determine the contribution of a single drug, in this case clofazimine, in a multidrug regimen to long-term clinical outcomes. That type of analysis would require larger studies with populations randomly assigned to similar regimens that contain or lack the drug of interest. To do so would also require modeling clofazimine MICs while controlling for all other potentially confounding factors, such as macrolide use or macrolide MIC. For example, in the present study, all five MAC converters (two with clofazimine MIC 0.25 μg/mL; one with MIC 0.5 μg/mL, and two with MIC 1.0 μg/mL) received macrolide-based therapy, which included twp patients with clofazimine MIC 0.25 μg/mL who received macrolide as initial therapy.1Kwak N. Whang J. Yang J.S. et al.Minimal inhibitory concentration of clofazimine among clinical isolates of nontuberculous mycobacteria and its impact on treatment outcome.Chest. 2021; 159: 517-523Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar Macrolide-containing regimens for MAC are associated with an approximately 80% chance of sputum conversion.12Wallace Jr., R.J. Brown-Elliott B.A. McNulty S. et al.Macrolide/azalide therapy for nodular/bronchiectatic Mycobacterium avium complex lung disease.Chest. 2014; 146: 276-282Abstract Full Text Full Text PDF PubMed Scopus (226) Google Scholar Additionally, the third drug added to macrolide and ethambutol, whether clofazimine or rifampin, does not appear to be a critical factor in sputum conversion and, in fact, may not be necessary at all.13Miwa S. Shirai M. Toyoshima M. et al.Efficacy of clarithromycin and ethambutol for Mycobacterium avium complex pulmonary disease: a preliminary study.Ann Am Thorac Soc. 2014; 11: 23-29Crossref PubMed Scopus (77) Google Scholar The analysis for patients with M abscessus is similarly complicated. One patient with M abscessus subsp massiliense converted with an initial macrolide-containing regimen. Macrolide-containing regimens are associated with up to 80% chance of sputum conversion for patients with M massiliense disease.14Choi G.E. Shin S.J. Won C.J. et al.Macrolide treatment for Mycobacterium abscessus and Mycobacterium massiliense infection and inducible resistance.Am J Respir Crit Care Med. 2012; 186: 917-925Crossref PubMed Scopus (135) Google Scholar Two patients with M abscessus subsp abscessus also converted with initial macrolide therapy. Although these isolates likely had inducible macrolide resistance, there is an approximate 20% chance that they were macrolide susceptible.15Brown-Elliott B.A. Vasireddy S. Vasireddy R. et al.Utility of sequencing the erm(41) gene in isolates of Mycobacterium abscessus subsp abscessus with low and intermediate clarithromycin MICs.J Clin Microbiol. 2015; 53: 1211-1215Crossref PubMed Scopus (101) Google Scholar Another challenge for the investigators of the analysis of Kwak et al1Kwak N. Whang J. Yang J.S. et al.Minimal inhibitory concentration of clofazimine among clinical isolates of nontuberculous mycobacteria and its impact on treatment outcome.Chest. 2021; 159: 517-523Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar was the large number of MAC and M abscessus isolates with MICs >0.5 μg/mL without prior clofazimine exposure. This is quite perplexing, because the high MICs noted in this study are consistent with the presence of resistance mechanisms beyond mutations simply influencing efflux pump activity. In our experience, isolates with such high clofazimine MICs are very unusual, which suggests the need to better understand the spectrum of resistance mechanisms at play in these isolates. The authors state that, on the basis of the present report, there is a correlation between clofazimine MICs and clinical outcome in NTM pulmonary disease.1Kwak N. Whang J. Yang J.S. et al.Minimal inhibitory concentration of clofazimine among clinical isolates of nontuberculous mycobacteria and its impact on treatment outcome.Chest. 2021; 159: 517-523Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar Although their data are intriguing, when viewed through the lens of the MIC principles listed earlier, it is clear that much more data are needed to evaluate fully a possible correlation between clofazimine MICs with clinical outcomes for both MAC and M abscessus lung disease. This study is a step forward in that process. You gotta make me see, what does it mean to have an MIC?16Junior Walker and the All-Stars. What does it take (to win your love for me). Detroit (MI): Tamia Motown. Released April 25, 1969.Google Scholar For clofazimine, we are still not sure. Minimal Inhibitory Concentration of Clofazimine Among Clinical Isolates of Nontuberculous Mycobacteria and Its Impact on Treatment OutcomeCHESTVol. 159Issue 2PreviewThe MICs of clofazimine varied widely in clinical isolates from patients with NTM-PD. Negative conversion of sputum culture with clofazimine use was associated with a lower MIC value. Clofazimine use could be considered in patients with NTM-PD when the MIC value is ≤ 0.25 mg/L. Full-Text PDF" @default.
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