scholarly journals 1350. Clofazimine as an Oral Companion Drug for Treatment of Mycobacterium abscessus complex Infections

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S488-S489
Author(s):  
Joy Yong ◽  
Ka Lip Chew ◽  
Paul Tambyah
Keyword(s):  
Active Agent ◽  
Liver Function Tests ◽  
Mycobacterium Abscessus ◽  
Prolonged Treatment ◽  
Attractive Alternative ◽  
In Vitro Susceptibility ◽  
Treatment Regimens ◽  
Drug Intolerance ◽  
Mycobacterium Abscessus Complex

Abstract Background Infections caused by the multi-drug-resistant Mycobacterium abscessus complex (MabsC) are challenging to treat and often require multiple antimicrobials for a prolonged treatment course and still have poor outcomes. Clofazimine, an oral anti-leprosy drug, has demonstrated good in vitro susceptibility and is being increasingly employed in treatment regimens for MabsC infections. We performed a drug-use-evaluation of clofazimine in the treatment of MabsC infections. Methods A retrospective review was performed for all patients with MabsC infections treated with clofazimine-containing regimens from January 2014 to June 2017. Results Twenty-nine patients were included. Twelve patients had pulmonary MabsC infections and seventeen had extrapulmonary infections. All isolates had clofazimine minimum-inhibitory-concentration of ≤0.5 mg/L as tested by broth microdilution. Clofazimine was prescribed at initiation of therapy in 31.0% (9/29), as a companion drug during maintenance therapy after initial intravenous therapy in 44.8% (13/29) and as part of salvage therapy due to disease progression or drug intolerance in 24.1% (7/29) of patients. Dosing of clofazimine for the pediatric patients was prescribed at 1–2 mg/kg/day while the adult patients received a range of 50–200 mg/day. Clofazimine was given for a median duration of 148.5 days (range: 14–1212) and most commonly in combination with clarithromycin (82.8%), amikacin (58.6%), and cefoxitin (24.1%). Twelve patients had documented adverse reactions attributable to clofazimine: skin hyperpigmentation (66.7%), abnormal liver function tests (16.7%), and gastrointestinal disturbance (16.7%). Table 1 describes the patients who had clofazimine ceased due to an adverse effect. Nine patients with pulmonary MabsC infections and 16 with extrapulmonary MabsC infections had documented improvement in symptoms. Conclusion Clofazimine as a companion drug in the treatment of MabsC infections was reasonably tolerated over a prolonged period of time. Its availability as an oral active agent makes it an attractive alternative to IV companion drugs and potentially improves compliance to the protracted treatment courses for patients with MabsC infections. Disclosures All authors: No reported disclosures.

In vitro susceptibility of Mycobacterium abscessus complex and feasibility of standardizing treatment regimens

2020 ◽  
Author(s):  
Ka Lip Chew ◽  
Sophie Octavia ◽  
Joelle Go ◽  
Sally Ng ◽  
Yit Er Tang ◽  
...  
Keyword(s):  
Retrospective Review ◽  
Susceptibility Testing ◽  
Mycobacterium Abscessus ◽  
In Vitro Activity ◽  
Broth Microdilution ◽  
In Vitro Susceptibility ◽  
Treatment Regimens ◽  
Mycobacterium Abscessus Complex ◽  
Additional Testing

Abstract Objectives To determine the in vitro susceptibility of members of the Mycobacterium abscessus complex to routinely tested antibiotics and to an extended antibiotic panel. Methods Non-duplicate isolates for which susceptibility testing results were available were included in this study. Retrospective laboratory records were reviewed, including tigecycline susceptibility results, and testing was performed with additional drugs, including vancomycin, dalbavancin, telavancin, oritavancin, rifabutin, delafloxacin, eravacycline, clofazimine and bedaquiline using broth microdilution (Sensititre, Thermo Fisher). Results A total of 218 M. abscessus complex isolates were included for retrospective review, of which 151 were respiratory isolates. Of these 218 isolates, 211 were available for additional testing with the extended antibiotic panel. Of these, 146 were respiratory isolates. One isolate had a vancomycin MIC of 2 mg/L and MICs of all other isolates were >8 mg/L. All isolates had MICs of >8 mg/L for oritavancin, dalbavancin and telavancin. One isolate had a delafloxacin MIC of 4 mg/L and MICs of all other isolates were >8 mg/L. The MIC50/MIC90s of rifabutin, tigecycline, eravacycline, clofazimine and bedaquiline were 16/32, 0.5/1, 0.12/0.25, 0.12/0.25 and 0.06/0.12 mg/L, respectively. Conclusions In vitro activity was demonstrated for clofazimine, bedaquiline and eravacycline, indicating potential for inclusion as standardized therapy for M. abscessus complex infections.

scholarly journals 1592. Antimicrobial Activity of Ceftazidime-Avibactam and Comparator Agents Against Enterobacterales and Pseudomonas aeruginosa With Overexpression of AmpC β-Lactamase From Phase 3 Clinical Trials

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S792-S793
Author(s):  
Lynn-Yao Lin ◽  
Dmitri Debabov ◽  
William Chang ◽  
Urania Rappo
Keyword(s):  
Clinical Trials ◽  
Active Agent ◽  
Complicated Urinary Tract Infection ◽  
Carbapenem Resistance ◽  
Vitro Activity ◽  
In Vitro Activity ◽  
Control Groups ◽  
In Vitro Susceptibility ◽  
Intra Abdominal Infection

Abstract Background AmpC overproduction is a main mechanism of carbapenem resistance, in the absence of acquired carbapenemases. Ceftazidime-avibactam (CAZ-AVI) has potent in vitro activity against AmpC-producing P. aeruginosa and Enterobacterales that are resistant to carbapenems and other β-lactams. Methods Activity of CAZ-AVI and comparators was evaluated against AmpC-overproducing Enterobacterales (n=77) and P. aeruginosa (n=53) collected from 4 CAZ-AVI clinical trials: RECLAIM (complicated intra-abdominal infection [cIAI]), REPRISE (cIAI/complicated urinary tract infection [cUTI]), RECAPTURE (cUTI) and REPROVE (hospital-acquired pneumonia/ventilator associated pneumonia). In vitro susceptibility of CAZ-AVI and comparators was performed by broth microdilution using ThermoFisher custom panels. CLSI breakpoints were used to determine susceptibility. Quantitative PCR and microarray data were used to characterize presence and expression of AmpC. Clinical response at test of cure was assessed. Results Against 77 AmpC-overproducing Enterobacterales isolates, meropenem-vaborbactam (MVB) (98.7% susceptible [S]), CAZ-AVI (96.1% S), and meropenem (MEM) (96.1% S) had similar in vitro activity (Table), with greater in vitro activity than amikacin (AMK) (84.4% S), gentamicin (61.0% S), and ceftolozane-tazobactam (TZC) (35.1% S). Clinical cures in patients with baseline AmpC-overproducing Enterobacterales were 21/26 (81%) in CAZ-AVI group vs 17/20 (85%) in control groups. Against 53 AmpC-overproducing P. aeruginosa isolates, CAZ-AVI (73.6% S) showed greater in vitro activity than AMK (69.8% S), TZC (58.5% S), and MEM (37.7% S). Clinical cures in patients with baseline AmpC-overproducing P. aeruginosa were 12/14 (86%) in CAZ-AVI group vs 9/12 (75%) in control groups. MIC distributions against the same P aeruginosa isolates were CAZ-AVI (MIC50/90, 4/ >64 µg/mL), MVB (MIC50/90, 8/32 µg/mL), and MEM (MIC50/90, 8/32 µg/mL). Table Conclusion CAZ-AVI was the most active agent against AmpC-overproducing P. aeruginosa with higher proportion of clinical cure than controls. CAZ-AVI was also among the most active agents against AmpC-overproducing Enterobacterales, with >96% isolates susceptible. Disclosures Lynn-Yao Lin, MS, AbbVie (Employee) Dmitri Debabov, PhD, AbbVie (Employee) William Chang, BS, AbbVie (Employee) Urania Rappo, MD, MS, PharmD, Allergan (before its acquisition by AbbVie) (Employee)

scholarly journals 1463. Activity of Delafloxacin against Multi-Drug-Resistant Fastidious Respiratory Pathogens from European Medical Centers (2014-2019)

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S733-S733
Author(s):  
Dee Shorttidge ◽  
Jennifer M Streit ◽  
Michael D Huband ◽  
Robert K Flamm
Keyword(s):  
Active Agent ◽  
The United States ◽  
Multidrug Resistant ◽  
Respiratory Pathogens ◽  
Services Research ◽  
In Vitro Susceptibility ◽  
Amoxicillin Clavulanate ◽  
Tract Infections ◽  
Research Grant

Abstract Background Delafloxacin (DLX) is an anionic fluoroquinolone (FQ) that has been approved in the United States and in Europe for the treatment of acute bacterial skin and skin structure infections and was recently approved in the US for treatment of community-acquired bacterial pneumonia (CABP). In the present study, in vitro susceptibility (S) results for DLX and comparator agents were determined for CABP pathogens including Streptococcus pneumoniae (SPN), Haemophilus influenzae (HI), H. parainfluenzae (HP) and Moraxella catarrhalis (MC) clinical isolates from European hospitals participating in the SENTRY Program during 2014-2019. Methods A total of 2,835 SPN, 1,484 HI, 959 MC, and 20 HP isolates were collected from community-acquired respiratory tract infections (CARTI) during 2014-2019 from European hospitals. Sites included only 1 isolate/patient/infection episode. Isolate identifications were confirmed at JMI Laboratories. Susceptibility testing was performed according to CLSI broth microdilution methodology, and EUCAST (2020) breakpoints were applied where applicable. Other antimicrobials tested included levofloxacin (LEV) and moxifloxacin (MOX; not tested in 2015). Multidrug-resistant (MDR) SPN isolates were categorized as being nonsusceptible (NS) to amoxicillin-clavulanate, erythromycin (ERY), and tetracycline; other SPN phenotypes were ERY-NS, or penicillin (PEN)-NS. β-lactamase (BL) presence was determined for HI, HP, and MC. Results The activities of the 3 FQs are shown in the table. The most active agent against SPN was DLX, with the lowest MIC50/90 values of 0.015/0.03 mg/L. DLX activities were the same when tested against the MDR or PEN-NS for SPN phenotypes. ERY-NS isolates had DLX MIC50/90 results of 0.015/0.03 mg/L. DLX was the most active FQ against HI, HP, and MC. BL presence did not affect FQ MIC values for HI or MC; only 1 HP isolate was BL-positive. Conclusion DLX demonstrated potent in vitro antibacterial activity against SPN, HI, HP, and MC. DLX was active against MDR SPN that were NS to the agents commonly used as treatments for CABP. These data support the utility of DLX in CABP including when caused by antibiotic resistant strains. Table 1 Disclosures Jennifer M. Streit, BS, A. Menarini Industrie Farmaceutiche Riunite S.R.L. (Research Grant or Support)A. Menarini Industrie Farmaceutiche Riunite S.R.L. (Research Grant or Support)Allergan (Research Grant or Support)Melinta Therapeutics, Inc. (Research Grant or Support)Melinta Therapeutics, Inc. (Research Grant or Support)Melinta Therapeutics, Inc. (Research Grant or Support)Merck (Research Grant or Support)Paratek Pharma, LLC (Research Grant or Support) Robert K. Flamm, PhD, A. Menarini Industrie Farmaceutiche Riunite S.R.L. (Research Grant or Support)Amplyx Pharmaceuticals (Research Grant or Support)Basilea Pharmaceutica International, Ltd (Research Grant or Support)Department of Health and Human Services (Research Grant or Support)Melinta Therapeutics, Inc. (Research Grant or Support)

scholarly journals Impact of susceptibility to injectable antibiotics on the treatment outcomes of Mycobacterium abscessus pulmonary disease

2021 ◽  
Author(s):  
Youngmok Park ◽  
Yea Eun Park ◽  
Byung Woo Jhun ◽  
Jimyung Park ◽  
Nakwon Kwak ◽  
...  
Keyword(s):  
Treatment Outcomes ◽  
Pulmonary Disease ◽  
Drug Susceptibility ◽  
Mycobacterium Abscessus ◽  
Beta Lactams ◽  
In Vitro Susceptibility ◽  
Referral Hospitals ◽  
Microbiological Cure ◽  
Culture Conversion

Abstract Objectives Current guidelines recommend a susceptibility-based regimen for Mycobacterium abscessus subspecies abscessus pulmonary disease (MAB-PD), but the evidence is weak. We aimed to investigate the association between treatment outcomes and in vitro drug susceptibility to injectable antibiotics in MAB-PD patients. Methods We enrolled MAB-PD patients treated with intravenous amikacin and beta-lactams for ≥4 weeks at four referral hospitals in Seoul, South Korea. Culture conversion and microbiological cure at one year were evaluated based on susceptibility to injectable antibiotics among patients treated with those antibiotics for ≥ 2 weeks. Results A total of 82 patients were analysed. The mean age was 58.7 years, and 65.9% were women. Sputum culture conversion and microbiological cure were achieved in 52.4% and 41.5% of patients, respectively. Amikacin was the most common agent to which the M. abscessus subspecies abscessus isolates were susceptible (81.7%); 9.8% and 24.0% of the isolates were resistant to cefoxitin and imipenem, respectively. The clarithromycin-inducible resistance (IR) group (n = 65) had a lower microbiological cure rate than the clarithromycin-susceptible group (35.4% vs. 64.7%). The treatment outcomes appeared to be similar regardless of in vitro susceptibility results with regard to intravenous amikacin, cefoxitin, imipenem, and moxifloxacin. In the subgroup analysis of the clarithromycin-IR group, the treatment outcomes did not differ according to antibiotic susceptibility. Conclusions We did not find evidence supporting the use of susceptibility-based treatment with intravenous amikacin and beta-lactams in patients with MAB-PD. Further research would be required.

scholarly journals 1582. Delafloxacin Activity Against Drug-Resistant Streptococcus pneumoniae, Haemophilus influenzae, Haemophilus parainfluenzae, and Moraxella catarrhalis from US Medical Centers (2014–2018)

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S577-S578
Author(s):  
Dee Shortridge ◽  
Jennifer M Streit ◽  
Michael D Huband ◽  
Robert K Flamm
Keyword(s):  
Streptococcus Pneumoniae ◽  
Haemophilus Influenzae ◽  
Moraxella Catarrhalis ◽  
Active Agent ◽  
The United States ◽  
Multidrug Resistant ◽  
In Vitro Susceptibility ◽  
Amoxicillin Clavulanate ◽  
Tract Infections

Abstract Background Delafloxacin (DLX) is an anionic fluoroquinolone (FQ) antimicrobial that was approved in 2017 by the United States (US) Food and Drug Administration for the treatment of acute bacterial skin and skin structure infections. DLX recently successfully completed a clinical trial for the treatment of community-acquired bacterial pneumonia (CABP). In the present study, in vitro susceptibility (S) results for DLX and comparator agents were determined for CABP pathogens including Streptococcus pneumoniae (SPN), Haemophilus influenzae (HI), H. parainfluenzae (HP) and Moraxella catarrhalis (MC) clinical isolates from US hospitals participating in the SENTRY Program during 2014–2018. Methods A total of 1,975 SPN, 1,128 HI, 684 MC, and 43 HP isolates were collected from community-acquired respiratory tract infections (CARTI) during 2014–2018 from US hospitals. Sites included only 1 isolate/patient/infection episode. Isolate identifications were confirmed at JMI Laboratories. Susceptibility testing was performed according to CLSI broth microdilution methodology, and CLSI (2019) breakpoints were applied where applicable. Other antimicrobials tested included levofloxacin (LEV) and moxifloxacin (MOX; not tested in 2015). Multidrug-resistant (MDR) SPN isolates were categorized as being nonsusceptible (NS) to amoxicillin-clavulanate, erythromycin, and tetracycline; other SPN phenotypes were LEV-NS or penicillin (PEN)-NS. β-Lactamase (BL) presence was determined for HI, HP, and MC. Results The activities of the 3 FQs are shown in the table. The most active agent against SPN was DLX, with the lowest MIC50/90 values of 0.015/0.03 mg/L. DLX activities were similar when tested against the MDR or PEN-NS for SPN phenotypes. LEV-NS isolates had DLX MIC50/90 results of 0.12/0.25 mg/L. DLX was the most active FQ against HI, HP, and MC. BL presence did not affect FQ MIC values for HI or MC; only 2 HP isolates were BL-positive. Conclusion DLX demonstrated potent in vitro antibacterial activity against SPN, HI, HP, and MC. DLX was active against MDR SPN that were NS to the agents commonly used as treatments for CABP. DLX had excellent activity against LEV-NS SPN. These data support the continued study of DLX as a potential treatment for CABP. Disclosures All authors: No reported disclosures.

scholarly journals In Vitro Susceptibility of Mycobacterium abscessus and Mycobacterium fortuitum Isolates to 30 Antibiotics

2018 ◽  
Vol 2018 ◽  
pp. 1-10 ◽  
Author(s):  
Yaojie Shen ◽  
Xuyang Wang ◽  
Jialin Jin ◽  
Jing Wu ◽  
Xuelian Zhang ◽  
...  
Keyword(s):  
Public Health Problem ◽  
Drug Susceptibility ◽  
Mycobacterium Abscessus ◽  
Mycobacterium Fortuitum ◽  
In Vitro Susceptibility ◽  
Antitubercular Drugs ◽  
Microdilution Method ◽  
Susceptibility Tests ◽  
Susceptibility Profiles

Objective. Nontuberculous mycobacteria (NTM) cause various diseases in humans and animals. Recently, the prevalence of NTM-related disease has been on the rise, becoming an emerging public health problem. The aim of this study was to determine the antibiotic susceptibility profiles of clinical isolates of Mycobacterium abscessus and Mycobacterium fortuitum. Methods. We performed susceptibility tests on 37 clinical NTM isolates to 30 antibiotics with the microdilution method recommended by the Clinical and Laboratory Standards Institute. Results. Both M. abscessus and M. fortuitum were highly resistant to antitubercular drugs such as isoniazid, rifampin, ethambutol, clofazimine, ethionamide, and rifabutin. M. abscessus showed the lowest resistant rates to cefoxitin (10%), azithromycin (10%), amikacin (10%), and clarithromycin (20%) and very high resistant to sulfamethoxazole, vancomycin, oxacillin, clindamycin, and all fluoroquinolones. M. fortuitum showed low resistance to tigecycline (0%), tetracycline (0%), cefmetazole (12%), imipenem (12%), linezolid (18%), and the aminoglycosides amikacin (0%), tobramycin (0%), neomycin (0%), and gentamycin (24%). Conclusion. Amikacin, cefoxitin, and azithromycin have the highest in vitro activity against M. abscessus. Isolates of M. fortuitum need to be individually evaluated for drug susceptibility before choosing an effective antimicrobial regimen for treatment of infections.

scholarly journals Evaluation of Ceftaroline-Avibactam Activity in vitro and ex vivo Against Mycobacterium abscessus Complex

2017 ◽  
Vol 4 (suppl_1) ◽  
pp. S675-S675 ◽  
Author(s):  
Ruchi Pandey ◽  
Liang Chen ◽  
Elena Shashkina ◽  
Claudia Manca ◽  
Robert A Bonomo ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Mycobacterium Abscessus ◽  
Mycobacterium Abscessus Complex

scholarly journals Artemisia annua and Artemisia afra extracts exhibit strong bactericidal activity against Mycobacterium tuberculosis

2020 ◽  
Author(s):  
Maria Carla Martini ◽  
Tianbi Zhang ◽  
John T. Williams ◽  
Robert B. Abramovitch ◽  
Pamela J. Weathers ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Bactericidal Activity ◽  
Artemisia Annua ◽  
Multidrug Resistant ◽  
Mycobacterium Abscessus ◽  
Major Barrier ◽  
Treatment Regimens ◽  
Tb Treatment ◽  
Emergence Of Resistance

ABSTRACTEthnopharmacological relevanceEmergence of drug-resistant and multidrug-resistant Mycobacterium tuberculosis (Mtb) strains is a major barrier to tuberculosis (TB) eradication, as it leads to longer treatment regimens and in many cases treatment failure. Thus, there is an urgent need to explore new TB drugs and combinations, in order to shorten TB treatment and improve outcomes. Here, we evaluate the potential of two medicinal plants, Artemisia annua, a natural source of artemisinin (AN), and Artemisia afra, as sources of novel antitubercular agents.Aim of the studyOur goal was to measure the activity of A. annua and A. afra extracts against Mtb as potential natural and inexpensive therapies for TB treatment, or as sources of compounds that could be further developed into effective treatments.Materials and MethodsThe minimum inhibitory concentrations (MICs) of A. annua and A. afra dichloromethane extracts were determined, and concentrations above the MICs were used to evaluate their ability to kill Mtb and Mycobacterium abscessus in vitro.ResultsPrevious studies showed that A. annua and A. afra inhibit Mtb growth. Here, we show for the first time that Artemisia extracts have a strong bactericidal activity against Mtb. The killing effect of A. annua was much stronger than equivalent concentrations of pure AN, suggesting that A. annua extracts kill Mtb through a combination of AN and additional compounds. A. afra, which produces very little AN, displayed bactericidal activity against Mtb that was substantial but weaker than that of A. annua. In addition, we measured the activity of Artemisia extracts against Mycobacterium abscessus. Interestingly, we observed that while A. annua is not bactericidal, it inhibits growth of M. abscessus, highlighting the potential of this plant in combinatory therapies to treat M. abscessus infections.ConclusionOur results indicate that Artemisia extracts have an enormous potential for treatment of TB and M. abscessus infections, and that these plants contain bactericidal compounds in addition to AN. Combination of extracts with existing antibiotics may not only improve treatment outcomes but also reduce the emergence of resistance to other drugs.

scholarly journals Differential in vitro activity of individual drugs and bedaquiline-rifabutin combinations against actively multiplying and nutrient-starved Mycobacterium abscessus

2020 ◽  
Author(s):  
Jin Lee ◽  
Nicole Ammerman ◽  
Anusha Agarwal ◽  
Maram Naji ◽  
Si-Yang Li ◽  
...  
Keyword(s):  
Bactericidal Activity ◽  
Treatment Options ◽  
Current Treatment ◽  
Mycobacterium Abscessus ◽  
Bacterial Populations ◽  
Treatment Regimens ◽  
Novel Treatment ◽  
Limited Effectiveness ◽  
Dependent Activity

AbstractCurrent treatment options for lung disease caused by Mycobacterium abscessus complex infections have limited effectiveness. To maximize the use of existing antibacterials and to help inform regimen design for treatment, we assessed the in vitro bactericidal activity of single drugs against actively multiplying and net non-replicating M. abscessus populations in nutrient-rich and nutrient starvation conditions, respectively. As single drugs, bedaquiline and rifabutin exerted bactericidal activity only against nutrient-starved and actively growing M. abscessus, respectively. However, when combined, both bedaquiline and rifabutin were able to specifically contribute bactericidal activity at relatively low, clinically relevant concentrations against both replicating and non-replicating bacterial populations. The addition of a third drug, amikacin, further enhanced the bactericidal activity of the bedaquiline-rifabutin combination against nutrient-starved M. abscessus. Overall, these in vitro data suggest that bedaquiline-rifabutin may be a potent backbone combination to support novel treatment regimens for M. abscessus infections. This rich dataset of differential time-and concentration-dependent activity of drugs, alone and together, against M. abscessus also highlights several issues affecting interpretation and translation of in vitro findings.

scholarly journals In Vitro Susceptibility Testing of GSK656 against Mycobacterium Species

2019 ◽  
Vol 64 (2) ◽  
Author(s):  
Wenzhu Dong ◽  
Shanshan Li ◽  
Shu’an Wen ◽  
Wei Jing ◽  
Jin Shi ◽  
...  
Keyword(s):  
Sequence Similarity ◽  
Binding Pocket ◽  
Trna Synthetase ◽  
Mycobacterium Abscessus ◽  
Drug Binding ◽  
Mycobacterial Species ◽  
In Vitro Susceptibility ◽  
Content Type ◽  
Sequence Variations

ABSTRACT In this study, we aimed to assess the in vitro susceptibility to GSK656 among multiple mycobacterial species and to investigate the correlation between leucyl-tRNA synthetase (LeuRS) sequence variations and in vitro susceptibility to GSK656 among mycobacterial species. A total of 187 mycobacterial isolates, comprising 105 Mycobacterium tuberculosis isolates and 82 nontuberculous mycobacteria (NTM) isolates, were randomly selected for the determination of in vitro susceptibility. For M. tuberculosis, 102 of 105 isolates had MICs of ≤0.5 mg/liter, demonstrating a MIC50 of 0.063 mg/liter and a MIC90 of 0.25 mg/liter. An epidemiological cutoff value of 0.5 mg/liter was proposed for identification of GSK656-resistant M. tuberculosis strains. For NTM, the MIC50 and MIC90 values were >8.0 mg/liter for both Mycobacterium intracellulare and Mycobacterium avium. In contrast, all Mycobacterium abscessus isolates had MICs of ≤0.25 mg/liter, yielding a MIC90 of 0.063 mg/liter. LeuRS from M. abscessus showed greater sequence similarity to M. tuberculosis LeuRS than to LeuRSs from M. avium and M. intracellulare. Sequence alignment revealed 28 residues differing between LeuRSs from M. avium and M. intracellulare and LeuRSs from M. tuberculosis and M. abscessus; among them, 15 residues were in the drug binding domain. Structure modeling revealed that several different residues were close to the tRNA-LeuRS interface or the entrance of the drug-tRNA binding pocket. In conclusion, our data demonstrate significant species diversity in in vitro susceptibility to GSK656 among various mycobacterial species. GSK656 has potent efficacy against M. tuberculosis and M. abscessus, whereas inherent resistance was noted for M. intracellulare and M. avium.

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