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

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.

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

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00440-18 ◽

2018 ◽

Vol 62 (10) ◽

Cited By ~ 9

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.

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Semimechanistic Pharmacokinetic/Pharmacodynamic Modeling of Fosfomycin and Sulbactam Combination against Carbapenem-Resistant Acinetobacter baumannii

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02472-20 ◽

2021 ◽

Vol 65 (5) ◽

Author(s):

Sazlyna Mohd Sazlly Lim ◽

Aaron J. Heffernan ◽

Jason A. Roberts ◽

Fekade B. Sime

Keyword(s):

Acinetobacter Baumannii ◽

Treatment Options ◽

Pharmacodynamic Modeling ◽

Synergistic Activity ◽

Bacterial Burden ◽

Target Attainment ◽

Content Type ◽

Carbapenem Resistant ◽

Time Kill

ABSTRACT Due to limited treatment options for carbapenem-resistant Acinetobacter baumannii (CR-AB) infections, antibiotic combinations are now considered potential treatments for CR-AB. This study aimed to explore the utility of fosfomycin-sulbactam combination (FOS/SUL) therapy against CR-AB isolates. Synergism of FOS/SUL against 50 clinical CR-AB isolates was screened using the checkerboard method. Thereafter, time-kill studies against two CR-AB isolates were performed. The time-kill data were described using a semimechanistic pharmacokinetic/pharmacodynamic (PK/PD) model. Monte Carlo simulations were then performed to estimate the probability of stasis, 1-log kill, and 2-log kill after 24 h of combination therapy. The FOS/SUL combination demonstrated a synergistic effect against 74% of isolates. No antagonism was observed. The MIC50 and MIC90 of FOS/SUL were decreased 4- to 8-fold, compared to the monotherapy MIC50 and MIC90. In the time-kill studies, the combination displayed bactericidal activity against both isolates and synergistic activity against one isolate at the highest clinically achievable concentrations. Our PK/PD model was able to describe the interaction between fosfomycin and sulbactam in vitro. Bacterial kill was mainly driven by sulbactam, with fosfomycin augmentation. FOS/SUL regimens that included sulbactam at 4 g every 8 h demonstrated a probability of target attainment of 1-log10 kill at 24 h of ∼69 to 76%, compared to ∼15 to 30% with monotherapy regimens at the highest doses. The reduction in the MIC values and the achievement of a moderate PTA of a 2-log10 reduction in bacterial burden demonstrated that FOS/SUL may potentially be effective against some CR-AB infections.

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Rifabutin Is Bactericidal against Intracellular and Extracellular Forms of Mycobacterium abscessus

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00363-20 ◽

2020 ◽

Vol 64 (11) ◽

Cited By ~ 2

Author(s):

Matt D. Johansen ◽

Wassim Daher ◽

Françoise Roquet-Banères ◽

Clément Raynaud ◽

Matthéo Alcaraz ◽

...

Keyword(s):

Opportunistic Pathogen ◽

Mycobacterium Abscessus ◽

Zebrafish Model ◽

Content Type ◽

Attractive Option ◽

Conventional Antibiotics ◽

Susceptibility Profiles ◽

Combination Regimens

ABSTRACT Mycobacterium abscessus is increasingly recognized as an emerging opportunistic pathogen causing severe lung diseases. As it is intrinsically resistant to most conventional antibiotics, there is an unmet medical need for effective treatments. Repurposing of clinically validated pharmaceuticals represents an attractive option for the development of chemotherapeutic alternatives against M. abscessus infections. In this context, rifabutin (RFB) has been shown to be active against M. abscessus and has raised renewed interest in using rifamycins for the treatment of M. abscessus pulmonary diseases. Here, we compared the in vitro and in vivo activity of RFB against the smooth and rough variants of M. abscessus, differing in their susceptibility profiles to several drugs and physiopathologial characteristics. While the activity of RFB is greater against rough strains than in smooth strains in vitro, suggesting a role of the glycopeptidolipid layer in susceptibility to RFB, both variants were equally susceptible to RFB inside human macrophages. RFB treatment also led to a reduction in the number and size of intracellular and extracellular mycobacterial cords. Furthermore, RFB was highly effective in a zebrafish model of infection and protected the infected larvae from M. abscessus-induced killing. This was corroborated by a significant reduction in the overall bacterial burden, as well as decreased numbers of abscesses and cords, two major pathophysiological traits in infected zebrafish. This study indicates that RFB is active against M. abscessus both in vitro and in vivo, further supporting its potential usefulness as part of combination regimens targeting this difficult-to-treat mycobacterium.

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Select β-Lactam Combinations Exhibit Synergy againstMycobacterium abscessus In Vitro

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02613-18 ◽

2019 ◽

Vol 63 (4) ◽

Cited By ~ 15

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.

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

10.1101/2020.10.14.340422 ◽

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.

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Synergistic Efficacy of β-Lactam Combinations againstMycobacterium abscessusPulmonary Infection in Mice

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00614-19 ◽

2019 ◽

Vol 63 (8) ◽

Cited By ~ 6

Author(s):

Elizabeth Story-Roller ◽

Emily C. Maggioncalda ◽

Gyanu Lamichhane

Keyword(s):

Acquired Resistance ◽

Mycobacterium Abscessus ◽

The Novel ◽

Content Type ◽

Treatment Regimens ◽

Chronic Lung Diseases ◽

Resistant Strains ◽

Drug Resistant Strains ◽

Inhibitor Combination

ABSTRACTMycobacterium abscessusis an emerging pathogen capable of causing invasive pulmonary infections in patients with chronic lung diseases. These infections are difficult to treat, necessitating prolonged multidrug therapy, which is further complicated by extensive intrinsic and acquired resistance exhibited by clinicalM. abscessusisolates. Therefore, development of novel treatment regimens effective against drug-resistant strains is crucial. Prior studies have demonstrated synergistic efficacy of several β-lactams againstM. abscessusin vitro; however, these combinations have never been tested in an animal model ofM. abscessuspulmonary disease. We utilized a recently developed murine system of sustainedM. abscessuslung infection delivered via an aerosol route to test the bactericidal efficacy of four novel dual β-lactam combinations and one β-lactam/β-lactamase inhibitor combination. All five of the novel combinations exhibited synergy and resulted in at least 6-log10reductions in bacterial burden in the lungs of mice at 4 weeks compared to untreated controls (P = 0.038).

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

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00470-19 ◽

2019 ◽

Vol 63 (6) ◽

Cited By ~ 23

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.

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

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00665-19 ◽

2019 ◽

Vol 63 (8) ◽

Cited By ~ 6

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.

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

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01503-18 ◽

2018 ◽

Vol 62 (11) ◽

Cited By ~ 13

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.

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

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02179-20 ◽

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

Current 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.

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