scholarly journals In VitroSusceptibility Testing of a Novel Benzimidazole, SPR719, against Nontuberculous Mycobacteria

2018 ◽  
Vol 62 (11) ◽  
Author(s):  
Barbara A. Brown-Elliott ◽  
Aileen Rubio ◽  
Richard J. Wallace
Keyword(s):  
Nontuberculous Mycobacteria ◽  
Treatment Options ◽  
Active Form ◽  
Mycobacterium Abscessus ◽  
Nontuberculous Mycobacterium ◽  
Content Type ◽  
Clinical Laboratories ◽  
Mueller Hinton ◽  
Mueller Hinton Broth

ABSTRACTNontuberculous mycobacterium (NTM) infections are increasing globally. TheMycobacterium aviumcomplex (MAC) andMycobacterium abscessusare the most frequently encountered NTM among clinical laboratories, and treatment options are extremely limited. In this study, thein vitropotency of a novel benzimidazole, SPR719, the microbiologically active form of the orally available prodrug SPR720, was tested against several species of NTM. MICs were determined for 161 isolates of NTM of 13 taxa (seven species, three subspecies, and three groups/complexes) in cation-adjusted Mueller-Hinton Broth, as described and recommended by the Clinical and Laboratory Standards Institute (CLSI M24-A2). Comparator antimicrobials included amikacin, cefoxitin, ciprofloxacin, clarithromycin, doxycycline, imipenem, linezolid, minocycline, moxifloxacin, tigecycline, and trimethoprim-sulfamethoxazole (TMP-SMX) for the rapidly growing mycobacteria (RGM), amikacin and clarithromycin for the MAC, and amikacin, ciprofloxacin, clarithromycin, doxycycline, linezolid, moxifloxacin, rifabutin, rifampin, and TMP-SMX for the other slowly growing NTM. SPR719 was found to be potent against multiple clinical strains of NTM with an MIC50range of 0.25 to 4 μg/ml for several species of NTM. These findings support the further advancement of SPR720 for the treatment of NTM disease.

scholarly journals Select β-Lactam Combinations Exhibit Synergy againstMycobacterium abscessus In Vitro

2019 ◽  
Vol 63 (4) ◽  
Author(s):  
Elizabeth Story-Roller ◽  
Emily C. Maggioncalda ◽  
Gyanu Lamichhane
Keyword(s):  
Treatment Options ◽  
Unmet Need ◽  
Mycobacterium Abscessus ◽  
Nontuberculous Mycobacterium ◽  
Pulmonary Infections ◽  
Content Type ◽  
Resistant Mutants ◽  
Lactamase Inhibitor ◽  
Selection Of

ABSTRACTMycobacterium abscessusis a nontuberculous mycobacterium that causes invasive pulmonary infections in patients with structural lung disease.M. abscessusis intrinsically resistant to several classes of antibiotics, and an increasing number of strains isolated from patients exhibit resistance to most antibiotics considered for treatment of infections by this mycobacterium. Therefore, there is an unmet need for new regimens with improved efficacy to treat this disease. Synthesis of the essential cell wall peptidoglycan inM. abscessusis achieved via two enzyme classes,l,d- andd,d-transpeptidases, with each class preferentially inhibited by different subclasses of β-lactam antibiotics. We hypothesized that a combination of two β-lactams that comprehensively inhibit the two enzyme classes will exhibit synergy in killingM. abscessus. Paired combinations of antibiotics tested forin vitrosynergy againstM. abscessusincluded dual β-lactams, a β-lactam and a β-lactamase inhibitor, and a β-lactam and a rifamycin. Of the initial 206 combinations screened, 24 pairs exhibited synergy. A total of 13/24 pairs were combinations of two β-lactams, and 12/24 pairs brought the MICs of both drugs to within the therapeutic range. Additionally, synergistic drug pairs significantly reduced the frequency of selection of spontaneous resistant mutants. These novel combinations of currently available antibiotics may offer viable immediate treatment options against highly-resistantM. abscessusinfections.

scholarly journals Comparison of In Vitro Susceptibility of Delafloxacin with Ciprofloxacin, Moxifloxacin, and other Comparator Antimicrobials Against Isolates of Nontuberculous Mycobacteria

2021 ◽  
Author(s):  
Barbara A. Brown Elliott ◽  
Richard J. Wallace
Keyword(s):  
Nontuberculous Mycobacteria ◽  
Oral Treatment ◽  
Treatment Options ◽  
In Vitro Susceptibility ◽  
Group 13 ◽  
Rapidly Growing Mycobacteria ◽  
Mueller Hinton ◽  
Group 5 ◽  
Mueller Hinton Broth

Nontuberculous mycobacteria (NTM) infections are increasing globally. Mycobacterium avium complex (MAC) and M. abscessus complex are the most commonly reported NTM. Oral treatment options are limited, especially for the M. abscessus. We tested delafloxacin, a new oral fluoroquinolone, against 131 isolates of NTM. Delafloxacin microdilution MICs were performed as recommended by the Clinical and Laboratory Standards Institute using cation adjusted Mueller Hinton broth. The rapidly growing mycobacteria tested included: M. abscessus subsp. abscessus (16) and subsp. massiliense (5), M. chelonae (11), M. immunogenum (5), M. fortuitum group (13), M. porcinum (7), M. senegalense (7), M. mucogenicum group (5), and M. goodii (1). For the slowly growing NTM (SGM), M. avium (16), M. intracellulare (13), M. chimaera (9), M. arupense (5), M. simiae (5), M. lentiflavum (4), M. kansasii (6), and M. marinum (3) were tested. Delafloxacin was most active in vitro against M. fortuitum and M. mucogenicum groups and M. kansasii with MIC50 values of 0.12-0.5 μg/mL (MIC range 0.001-4 μg/mL) compared to ≤0.06->4 μg/mL for ciprofloxacin and ≤0.06->8 μg/mL for moxifloxacin. For other SGM (including MAC), and the M. abscessus/chelonae, the delafloxacin MIC range was 8->16 μg/mL compared to ciprofloxacin and moxifloxacin of 0.5->4 μg/mL and ≤0.06-8 μg/mL, respectively. To our knowledge, this is the first MIC study with delafloxacin to use Clinical and Laboratory Standards Institute (CLSI) recommended methods. This study illustrates the potential utility of delafloxacin in treatment of infections due to some NTM.

scholarly journals Effective Treatment of Mycobacterium avium subsp. hominissuis and Mycobacterium abscessus Species Infections in Macrophages, Biofilm, and Mice by Using Liposomal Ciprofloxacin

2018 ◽  
Vol 62 (10) ◽  
Author(s):  
James D. Blanchard ◽  
Valerie Elias ◽  
David Cipolla ◽  
Igor Gonda ◽  
Luiz E. Bermudez
Keyword(s):  
Effective Treatment ◽  
Mouse Models ◽  
Mycobacterium Avium ◽  
Nontuberculous Mycobacteria ◽  
Mycobacterium Abscessus ◽  
Content Type ◽  
Number Of Individuals ◽  
Intranasal Instillation

ABSTRACT Nontuberculous mycobacteria (NTM) affect an increasing number of individuals worldwide. Infection with these organisms is more common in patients with chronic lung conditions, and treatment is challenging. Quinolones, such as ciprofloxacin, have been used to treat patients, but the results have not been encouraging. In this report, we evaluate novel formulations of liposome-encapsulated ciprofloxacin (liposomal ciprofloxacin) in vitro and in vivo. Its efficacy against Mycobacterium avium and Mycobacterium abscessus was examined in macrophages, in biofilms, and in vivo using intranasal instillation mouse models. Liposomal ciprofloxacin was significantly more active than free ciprofloxacin against both pathogens in macrophages and biofilms. When evaluated in vivo, treatment with the liposomal ciprofloxacin formulations was associated with significant decreases in the bacterial loads in the lungs of animals infected with M. avium and M. abscessus. In summary, topical delivery of liposomal ciprofloxacin in the lung at concentrations greater than those achieved in the serum can be effective in the treatment of NTM, and further evaluation is warranted.

scholarly journals In Vitro Activity of the Siderophore Cephalosporin, Cefiderocol, against a Recent Collection of Clinically Relevant Gram-Negative Bacilli from North America and Europe, Including Carbapenem-Nonsusceptible Isolates (SIDERO-WT-2014 Study)

2017 ◽  
Vol 61 (9) ◽  
Author(s):  
Meredith A. Hackel ◽  
Masakatsu Tsuji ◽  
Yoshinori Yamano ◽  
Roger Echols ◽  
James A. Karlowsky ◽  
...  
Keyword(s):  
North America ◽  
North American ◽  
Clinical Isolates ◽  
In Vitro Activity ◽  
Gram Negative ◽  
Content Type ◽  
Mueller Hinton ◽  
Recent Collection ◽  
Mueller Hinton Broth

ABSTRACT Cefiderocol (formerly S-649266) is an investigational siderophore cephalosporin. Iron-depleted cation-adjusted Mueller-Hinton broth (ID-CAMHB) was prepared according to the Clinical and Laboratory Standards Institute (CLSI) protocol and used to perform broth microdilution testing of cefiderocol against a 2014-2015 collection of clinical isolates of Gram-negative bacilli from North America (n = 4,239) and Europe (n = 4,966). The concentrations of cefiderocol inhibiting 90% of isolates tested (MIC90s) were 0.5 μg/ml (North America; n = 3,007) and 1 μg/ml (Europe; n = 3,080) for all isolates of Enterobacteriaceae; 1 μg/ml (North America; n = 30) and 4 μg/ml (Europe; n = 139) for meropenem-nonsusceptible (MIC ≥ 2 μg/ml) isolates of Enterobacteriaceae; 0.5 μg/ml for both North American (n = 765) and European (n = 765) isolates of Pseudomonas aeruginosa; 0.5 μg/ml (North America; n = 151) and 1 μg/ml (Europe; n = 202) for meropenem-nonsusceptible (MIC ≥ 4 μg/ml) isolates of P. aeruginosa; 1 μg/ml for both North American (n = 309) and European (n = 839) isolates of all Acinetobacter baumannii strains as well as for both North American (n = 173) and European (n = 595) isolates of meropenem-nonsusceptible A. baumannii; and 0.5μg/ml (North America; n = 152) and 0.25 μg/ml (Europe; n = 276) for isolates of Stenotrophomonas maltophilia. MICs of cefiderocol were ≤4 μg/ml for 99.9% (6,078/6,087) of all Enterobacteriaceae, 97.0% (164/169) of meropenem-nonsusceptible Enterobacteriaceae, 99.9% (1,529/1,530) of all P. aeruginosa isolates, 100% (353/353) of meropenem-nonsusceptible P. aeruginosa isolates, 97.6% (1,120/1,148) of all A. baumannii isolates, 96.9% (744/768) of meropenem-nonsusceptible A. baumannii isolates, 100% of isolates of S. maltophilia (428/428) and 93.8% of isolates of Burkholderia cepecia (11/12). We conclude that cefiderocol demonstrated potent in vitro activity against a recent collection of clinical isolates of commonly encountered Gram-negative bacilli, including carbapenem-nonsusceptible isolates.

scholarly journals In Vitro Activity of New Tetracycline Analogs Omadacycline and Eravacycline against Drug-Resistant Clinical Isolates of Mycobacterium abscessus

2019 ◽  
Vol 63 (6) ◽  
Author(s):  
Amit Kaushik ◽  
Nicole C. Ammerman ◽  
Olumide Martins ◽  
Nicole M. Parrish ◽  
Eric L. Nuermberger
Keyword(s):  
Salvage Therapy ◽  
Treatment Options ◽  
Oral Formulation ◽  
Mycobacterium Abscessus ◽  
Clinical Isolates ◽  
Drug Resistant ◽  
In Vitro Activity ◽  
Content Type ◽  
New Treatment

ABSTRACT Tigecycline is used in multidrug regimens for salvage therapy of Mycobacterium abscessus infections but is often poorly tolerated and has no oral formulation. Here, we report similar in vitro activity of two newly approved tetracycline analogs, omadacycline and eravacycline, against 28 drug-resistant clinical isolates of M. abscessus complex. Since omadacycline and eravacycline appear to be better tolerated than tigecycline and since omadacycline is also formulated for oral dosing, these tetracycline analogs may represent new treatment options for M. abscessus infections.

scholarly journals Clofazimine Prevents the Regrowth of Mycobacterium abscessus and Mycobacterium avium Type Strains Exposed to Amikacin and Clarithromycin

2015 ◽  
Vol 60 (2) ◽  
pp. 1097-1105 ◽  
Author(s):  
Beatriz E. Ferro ◽  
Joseph Meletiadis ◽  
Melanie Wattenberg ◽  
Arjan de Jong ◽  
Dick van Soolingen ◽  
...  
Keyword(s):  
Mycobacterium Avium ◽  
Treatment Options ◽  
Mycobacterium Abscessus ◽  
Surface Model ◽  
Target Attainment ◽  
Content Type ◽  
Treatment Regimens ◽  
Combination Regimens ◽  
Type Strains

ABSTRACTMultidrug therapy is a standard practice when treating infections by nontuberculous mycobacteria (NTM), but few treatment options exist. We conducted this study to define the drug-drug interaction between clofazimine and both amikacin and clarithromycin and its contribution to NTM treatment.Mycobacterium abscessusandMycobacterium aviumtype strains were used. Time-kill assays for clofazimine alone and combined with amikacin or clarithromycin were performed at concentrations of 0.25× to 2× MIC. Pharmacodynamic interactions were assessed by response surface model of Bliss independence (RSBI) and isobolographic analysis of Loewe additivity (ISLA), calculating the percentage of statistically significant Bliss interactions and interaction indices (I), respectively. Monte Carlo simulations with predicted human lung concentrations were used to calculate target attainment rates for combination and monotherapy regimens. Clofazimine alone was bacteriostatic for both NTM. Clofazimine-amikacin was synergistic againstM. abscessus(I = 0.41; 95% confidence interval [CI], 0.29 to 0.55) andM. avium(I = 0.027; 95% CI, 0.007 to 0.048). Based on RSBI analysis, synergistic interactions of 28.4 to 29.0% and 23.2 to 56.7% were observed at 1× to 2× MIC and 0.25× to 2× MIC forM. abscessusandM. avium, respectively. Clofazimine-clarithromycin was also synergistic againstM. abscessus(I = 0.53; 95% CI, 0.35 to 0.72) andM. avium(I = 0.16; 95% CI, 0.04 to 0.35), RSBI analysis showed 23.5% and 23.3 to 53.3% at 2× MIC and 0.25× to 0.5× MIC forM. abscessusandM. avium, respectively. Clofazimine prevented the regrowth observed with amikacin or clarithromycin alone. Target attainment rates of combination regimens were >60% higher than those of monotherapy regimens forM. abscessusandM. avium. The combination of clofazimine with amikacin or clarithromycin was synergisticin vitro. This suggests a potential role for clofazimine in treatment regimens that warrants further evaluation.

scholarly journals Two-Site Evaluation of the Colistin Broth Disk Elution Test To Determine Colistin In Vitro Activity against Gram-Negative Bacilli

2018 ◽  
Vol 57 (2) ◽  
Author(s):  
Patricia J. Simner ◽  
Yehudit Bergman ◽  
Marisol Trejo ◽  
Ava A. Roberts ◽  
Remy Marayan ◽  
...  
Keyword(s):  
Growth Control ◽  
Practical Method ◽  
Clinical Isolates ◽  
Gram Negative ◽  
Content Type ◽  
Mueller Hinton ◽  
Site Evaluation ◽  
Broth Macrodilution ◽  
Mueller Hinton Broth

ABSTRACT Limited methods for colistin MIC determination are available to clinical microbiology laboratories. The purpose of this study was to evaluate the accuracy of the colistin broth disk elution (CBDE) test compared to that of broth microdilution (BMD) for identifying colistin MICs. CBDE was compared to colistin BMD using a collection of Gram-negative bacilli tested at two U.S. microbiology laboratories. The isolates tested included 121 retrospective clinical isolates, 45 prospective clinical isolates, and 6 mcr-1-positive Escherichia coli isolates. CBDE was performed with four 10-ml cation-adjusted Mueller-Hinton broth tubes per isolate, to which 0, 1, 2, and 4 colistin 10-µg disks were added, generating final concentrations in the tubes of 0 (growth control), 1, 2, and 4 µg/ml, respectively. MICs were evaluated visually and interpreted using Clinical and Laboratory Standards Institute breakpoints. Site 2 also compared CBDE to the reference broth macrodilution (BMAD) method (n = 110 isolates). Overall, CBDE yielded a categorical agreement (CA) and essential agreement (EA) of 98% and 99%, respectively, compared to the results of colistin BMD. Very major errors occurred for mcr-1-producing strains, with MICs fluctuating from 2 to 4 µg/ml on repeat testing. The results for all other isolates were in CA with those of BMD. CBDE versus BMAD had an EA of 100% and a CA of 100%. Compared to currently used techniques, CBDE is an easy and practical method to perform colistin MIC testing. Some mcr-1-producing isolates yielded MICs of 2 µg/ml by CBDE and 4 µg/ml by BMD. As such, the results for isolates with colistin MICs of 2 µg/ml by CBDE should be confirmed by the reference BMD method, and isolates with MICs of ≥2 µg/ml should be evaluated for the presence of mcr genes.

scholarly journals Screening of Preselected Libraries TargetingMycobacterium abscessusfor Drug Discovery

2018 ◽  
Vol 62 (9) ◽  
Author(s):  
Adrian Richter ◽  
Angelika Strauch ◽  
Joseph Chao ◽  
Mary Ko ◽  
Yossef Av-Gay
Keyword(s):  
Drug Discovery ◽  
Drug Screening ◽  
Mycobacterium Abscessus ◽  
Growth Media ◽  
Content Type ◽  
Screening Approach ◽  
Mueller Hinton ◽  
The Impact ◽  
First Time ◽  
Mueller Hinton Broth

ABSTRACTMycobacterium abscessusis intrinsically resistant to many antimycobacterial antibiotics, which presents serious problems in therapy. Here, we describe the development of a novel phenotype-based microscopic and computerized imaging drug screening approach. A pilot screen of 568 compounds from two libraries identified 17 hits. Eleven of these compounds are described for the first time as active againstM. abscessus. The impact of growth media on the activity of these compounds was tested, revealing that cation-adjusted Mueller-Hinton broth (MHII) supports better growth of actively replicatingM. abscessusand improves the activity of associated compounds.

scholarly journals In Vitro Activity of Bedaquiline and Delamanid against Nontuberculous Mycobacteria, Including Macrolide-Resistant Clinical Isolates

2019 ◽  
Vol 63 (8) ◽  
Author(s):  
Dae Hun Kim ◽  
Byung Woo Jhun ◽  
Seong Mi Moon ◽  
Su-Young Kim ◽  
Kyeongman Jeon ◽  
...  
Keyword(s):  
Mycobacterium Avium ◽  
Nontuberculous Mycobacteria ◽  
Mycobacterium Abscessus ◽  
Vitro Activity ◽  
Clinical Isolates ◽  
In Vitro Activity ◽  
Mycobacterium Kansasii ◽  
Antimicrobial Drugs ◽  
Content Type

ABSTRACT We evaluated the in vitro activities of the antimicrobial drugs bedaquiline and delamanid against the major pathogenic nontuberculous mycobacteria (NTM). Delamanid showed high MIC values for all NTM except Mycobacterium kansasii. However, bedaquiline showed low MIC values for the major pathogenic NTM, including Mycobacterium avium complex, Mycobacterium abscessus subsp. abscessus, M. abscessus subsp. massiliense, and M. kansasii. Bedaquiline also had low MIC values with macrolide-resistant NTM strains and warrants further investigation as a potential antibiotic for NTM treatment.

scholarly journals Pharmacodynamic Profiling of a Siderophore-Conjugated Monocarbam in Pseudomonas aeruginosa: Assessing the Risk for Resistance and Attenuated Efficacy

2015 ◽  
Vol 59 (12) ◽  
pp. 7743-7752 ◽  
Author(s):  
Aryun Kim ◽  
Amy Kutschke ◽  
David E. Ehmann ◽  
Sara A. Patey ◽  
Jared L. Crandon ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Body Weight ◽  
Iron Uptake ◽  
Threshold Concentration ◽  
Content Type ◽  
Adaptive Resistance ◽  
Mueller Hinton ◽  
Mueller Hinton Broth

ABSTRACTThe objective of this study was to investigate the risk of attenuated efficacy due to adaptive resistance for the siderophore-conjugated monocarbam SMC-3176 inPseudomonas aeruginosaby using a pharmacokinetic/pharmacodynamic (PK/PD) approach. MICs were determined in cation-adjusted Mueller-Hinton broth (MHB) and in Chelex-treated, dialyzed MHB (CDMHB). Spontaneous resistance was assessed at 2× to 16× the MIC and the resulting mutants sequenced. Efficacy was evaluated in a neutropenic mouse thigh model at 3.13 to 400 mg/kg of body weight every 3 h for 24 h and analyzed for association with free time above the MIC (fT>MIC). To closer emulate the conditions of thein vivomodel, we developed a novel assay testing activity mouse whole blood (WB). All mutations were found in genes related to iron uptake:piuA,piuC,pirR,fecI, andpvdS. Against fourP. aeruginosaisolates, SMC-3176 displayed predictable efficacy corresponding to thefT>MIC using the MIC in CDMHB (R2= 0.968 to 0.985), with stasis to 2-log kill achieved at 59.4 to 81.1%. Efficacy did not translate forP. aeruginosaisolate JJ 4-36, as thein vivoresponses were inconsistent withfT>MIC exposures and implied a threshold concentration that was greater than the MIC. The results of the mouse WB assay indicated that efficacy was not predictable using the MIC for JJ 4-36 and four additional isolates, against whichin vivofailures of another siderophore-conjugated β-lactam were previously reported. SMC-3176 carries a risk of attenuated efficacy inP. aeruginosadue to rapid adaptive resistance preventing entry via the siderophore-mediated iron uptake systems. Substantialin vivotesting is warranted for compounds using the siderophore approach to thoroughly screen for thisin vitro-in vivodisconnect inP. aeruginosa.

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