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 Select β-lactam combinations exhibit synergy against Mycobacterium abscessus in vitro

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

ABSTRACTMycobacterium abscessus (Mab) is a nontuberculous mycobacterium that causes invasive pulmonary infections in patients with structural lung disease. Mab is 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 Mab infections. Therefore, there is an unmet need for new regimens with improved efficacy to treat this disease. Synthesis of the essential cell wall peptidoglycan in Mab is achieved via two enzyme classes, L,D- and D-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 killing Mab. Paired combinations of antibiotics tested for in vitro synergy against Mab included 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. 13/24 pairs were combinations of two β-lactams. 12/24 pairs brought the minimum inhibitory concentrations 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-resistant Mab infections.

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 In Vitro and Intracellular Activity of Imipenem Combined with Rifabutin and Avibactam against Mycobacterium abscessus

2018 ◽  
Vol 62 (8) ◽  
Author(s):  
Eva Le Run ◽  
Michel Arthur ◽  
Jean-Luc Mainardi
Keyword(s):  
Inhibitory Concentration ◽  
Mycobacterium Abscessus ◽  
Antibiotic Activity ◽  
Intracellular Bacteria ◽  
Triple Combination ◽  
Pulmonary Infections ◽  
Content Type ◽  
The Impact ◽  
Lactamase Inhibitor

ABSTRACT Repurposing drugs may be useful as an add-on in the treatment of Mycobacterium abscessus pulmonary infections, which are particularly difficult to cure. M. abscessus naturally produces a β-lactamase, BlaMAb, which is inhibited by avibactam. The recommended regimens include imipenem, which is hydrolyzed by BlaMAb and used without any β-lactamase inhibitor. Here, we determine whether the addition of rifabutin improves the activity of imipenem alone or in combination with avibactam against M. abscessus CIP104536. Rifabutin at 16 μg/ml was only bacteriostatic (MIC of 4 μg/ml) and was moderately synergistic in combination with imipenem (fractional inhibitory concentration [FIC] index of 0.38). Addition of rifabutin (16 μg/ml) moderately increased killing by a low (8 μg/ml) but not by a high (32 μg/ml) concentration of imipenem. Addition of avibactam (4 μg/ml) did not further increase killing by the former combination. In infected macrophages, rifabutin (16 μg/ml) increased the activity of imipenem at 8 and 32 μg/ml, achieving 3- and 100-fold reductions in the numbers of intracellular bacteria, respectively. Avibactam (16 μg/ml) improved killing by imipenem at 8 μg/ml. A 5-fold killing was obtained for a triple combination comprising avibactam (16 μg/ml) and therapeutically achievable doses of imipenem (8 μg/ml) and rifabutin (1 μg/ml). These results indicate that the imipenem-rifabutin combination should be further considered for the treatment of M. abscessus pulmonary infections in cystic fibrosis patients and that addition of a β-lactamase inhibitor might improve its efficacy. Mechanistically, the impact of BlaMAb inhibition by avibactam on antibiotic activity was assessed by comparing CIP104536 and a β-lactamase-deficient derivative.

scholarly journals In vitro and intracellular activity of imipenem combined with tedizolid, rifabutin, and avibactam against Mycobacterium abscessus

2018 ◽  
Author(s):  
Eva Le Run ◽  
Michel Arthur ◽  
Jean-Luc Mainardi
Keyword(s):  
Inhibitory Concentration ◽  
Antibacterial Activities ◽  
Mycobacterium Abscessus ◽  
Pulmonary Infections ◽  
Once Daily ◽  
Minimal Inhibitory Concentrations ◽  
Recommended Treatment ◽  
The Impact ◽  
Lactamase Inhibitor

Mycobacterium abscessus has emerged as a significant pathogen responsible for chronic pulmonary infections in cystic fibrosis (CF) patients, which are difficult to treat due to resistance to a broad range of antibiotics. The initial phase of the recommended treatment in CF patients includes imipenem used without any β-lactamase inhibitor in spite of the production of the β-lactamase BlaMab. Here, we determine whether the addition of tedizolid, a once-daily oxazolidinone, improves the activity of imipenem alone or in combination with a β-lactamase inhibitor, avibactam, and rifabutin.The activity of the drugs was evaluated against M. abscessus CIP104536 by determining in vitro and intracellular antibacterial activities. The impact of BlaMab inhibition by avibactam on antibiotic activity was assessed by comparing CIP104536 and its β-lactamase-deficient derivative (ΔblaMab).The minimal inhibitory concentrations (MICs) of tedizolid against M. abscessus CIP104536 and ΔblaMab were 4 μg/mL. Tedizolid combined with imipenem showed a moderate synergistic effect with fractional inhibitory concentration (FIC) indexes of 0.41 and 0.38 for CIP104536 and ΔblaMab, respectively. For both strains, the addition of tedizolid at 2 μg/mL, corresponding to the peak serum concentration, increased the intracellular efficacy of imipenem at 8 and 32 μg/mL. Addition of avibactam and rifabutin improved the activity of the imipenem-tedizolid combination against CIP104536S.The imipenem-tedizolid combination should be further considered for the treatment of M. abscessus pulmonary infections in CF patients. The efficacy of the treatment might benefit from the use of a β-lactamase inhibitor, such as avibactam, and the addition of rifabutin.

scholarly journals Rifabutin Acts in Synergy and Is Bactericidal with FrontlineMycobacterium abscessusAntibiotics Clarithromycin and Tigecycline, Suggesting a Potent Treatment Combination

2018 ◽  
Vol 62 (8) ◽  
Author(s):  
Mark Pryjma ◽  
Ján Burian ◽  
Charles J. Thompson
Keyword(s):  
Treatment Options ◽  
Multidrug Resistant ◽  
Current Treatment ◽  
Mycobacterium Abscessus ◽  
Triple Combination ◽  
Pulmonary Infections ◽  
Treatment Combination ◽  
Content Type ◽  
Current Treatment Regimen ◽  
Drug Regimens

ABSTRACTMycobacterium abscessusis a rapidly emerging mycobacterial pathogen causing dangerous pulmonary infections. Because these bacteria are intrinsically multidrug resistant, treatment options are limited and have questionable efficacy. The current treatment regimen relies on a combination of antibiotics, including clarithromycin paired with amikacin and either imipenem or cefoxitin. Tigecycline may be added when triple therapy is ineffective. We initially screened a library containing the majority of clinically available antibiotics for anti-M. abscessusactivity. The screen identified rifabutin, which was then investigated for its interactions withM. abscessusantibiotics used in drug regimens. Combination of rifabutin with either clarithromycin or tigecycline generated synergistic anti-M. abscessusactivity, dropping the rifabutin MIC below concentrations found in the lung. Importantly, these combinations generated bactericidal activity. The triple combination of clarithromycin, tigecycline, and rifabutin was also synergistic, and clinically relevant concentrations had a sterilizing effect onM. abscessuscultures. We suggest that combinations including rifabutin should be further investigated for treatment ofM. abscessuspulmonary infections.

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 Verapamil Improves the Activity of Bedaquiline against Mycobacterium abscessus In Vitro and in Macrophages

2019 ◽  
Vol 63 (9) ◽  
Author(s):  
Albertus Viljoen ◽  
Clément Raynaud ◽  
Matt D. Johansen ◽  
Françoise Roquet-Banères ◽  
Jean-Louis Herrmann ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Adjunctive Therapy ◽  
Mycobacterium Abscessus ◽  
Pulmonary Infections ◽  
Content Type ◽  
Resistant Strains ◽  
High Doses ◽  
Clinical Potential

ABSTRACT Due to intrinsic multidrug resistance, pulmonary infections with Mycobacterium abscessus are extremely difficult to treat. Previously, we demonstrated that bedaquiline is highly effective against Mycobacterium abscessus both in vitro and in vivo. Here, we report that verapamil improves the efficacy of bedaquiline activity against M. abscessus clinical isolates and low-level resistant strains, both in vitro and in macrophages. Verapamil may have clinical potential as adjunctive therapy provided that sufficiently high doses can be safely achieved.

scholarly journals In VitroActivity of Delafloxacin against Clinical Neisseria gonorrhoeae Isolates and Selection of Gonococcal Delafloxacin Resistance

2016 ◽  
Vol 60 (5) ◽  
pp. 3106-3111 ◽  
Author(s):  
Olusegun O. Soge ◽  
Stephen J. Salipante ◽  
David No ◽  
Erin Duffy ◽  
Marilyn C. Roberts
Keyword(s):  
Neisseria Gonorrhoeae ◽  
Spontaneous Mutation ◽  
Efflux Pumps ◽  
Multidrug Resistant ◽  
Cross Resistance ◽  
Content Type ◽  
Resistant Mutants ◽  
Reference Strains ◽  
Selection Of

ABSTRACTWe evaluated thein vitroactivity of delafloxacin against a panel of 117Neisseria gonorrhoeaestrains, including 110 clinical isolates collected from 2012 to 2015 and seven reference strains, compared with the activities of seven antimicrobials currently or previously recommended for treatment of gonorrhea. We examined the potential for delafloxacin to select for resistant mutants in ciprofloxacin-susceptible and ciprofloxacin-resistantN. gonorrhoeae. We characterized mutations in thegyrA,gyrB,parC, andparEgenes and the multidrug-resistant efflux pumps (MtrC-MtrD-MtrE and NorM) by PCR and sequencing and by whole-genome sequencing. The MIC50, MIC90, and MIC ranges of delafloxacin were 0.06 μg/ml, 0.125 μg/ml, and ≤0.001 to 0.25 μg/ml, respectively. The frequency of spontaneous mutation ranged from 10−7to <10−9. The multistep delafloxacin resistance selection of 30 daily passages resulted in stable resistant mutants. There was no obvious cross-resistance to nonfluoroquinolone comparator antimicrobials. A mutant with reduced susceptibility to ciprofloxacin (MIC, 0.25 μg/ml) obtained from the ciprofloxacin-susceptible parental strain had a novel Ser91Tyr alteration in thegyrAgene. We also identified new mutations in thegyrAand/orparCandparEgenes and the multidrug-resistant efflux pumps (MtrC-MtrD-MtrE and NorM) of two mutant strains with elevated delafloxacin MICs of 1 μg/ml. Although delafloxacin exhibited potentin vitroactivity againstN. gonorrhoeaeisolates and reference strains with diverse antimicrobial resistance profiles and demonstrated a low tendency to select for spontaneous mutants, it is important to establish the correlation between these excellentin vitrodata and treatment outcomes through appropriate randomized controlled clinical trials.

scholarly journals Bedaquiline Inhibits the ATP Synthase in Mycobacterium abscessus and Is Effective in Infected Zebrafish

2017 ◽  
Vol 61 (11) ◽  
Author(s):  
Christian Dupont ◽  
Albertus Viljoen ◽  
Sangeeta Thomas ◽  
Françoise Roquet-Banères ◽  
Jean-Louis Herrmann ◽  
...  
Keyword(s):  
Atp Synthase ◽  
Multidrug Resistant ◽  
Mycobacterium Abscessus ◽  
Nucleotide Polymorphisms ◽  
Pulmonary Infections ◽  
Zebrafish Model ◽  
Content Type ◽  
Short Period

ABSTRACT Pulmonary infections caused by Mycobacterium abscessus are emerging as a global threat, especially in cystic fibrosis patients. Further intensifying the concern of M. abscessus infection is the recent evidence of human-to-human transmission of the infection. M. abscessus is a naturally multidrug-resistant fast-growing pathogen for which pharmacological options are limited. Repurposing antitubercular drugs represents an attractive option for the development of chemotherapeutic alternatives against M. abscessus infections. Bedaquiline (BDQ), an ATP synthase inhibitor, has recently been approved for the treatment of multidrug-resistant tuberculosis. Herein, we show that BDQ has a very low MIC against a vast panel of clinical isolates. Despite being bacteriostatic in vitro, BDQ was highly efficacious in a zebrafish model of M. abscessus infection. Remarkably, a very short period of treatment was sufficient to protect the infected larvae from M. abscessus-induced killing. This was corroborated with reduced numbers of abscesses and cords, considered to be major pathophysiological signs in infected zebrafish. Mode-of-action studies revealed that BDQ triggered a rapid depletion of ATP in M. abscessus in vitro, consistent with the drug targeting the FoF1 ATP synthase. Importantly, despite a failure to select in vitro for spontaneous mutants that are highly resistant to BDQ, the transfer of single nucleotide polymorphisms leading to D29V or A64P substitutions in atpE conferred high resistance, thus resolving the target of BDQ in M. abscessus. Overall, this study indicates that BDQ is active against M. abscessus in vitro and in vivo and should be considered for clinical use against the difficult-to-manage M. abscessus pulmonary infections.

Sign in / Sign up

Export Citation Format

Share Document