Dataset Information

Inhaled tigecycline is effective against Mycobacterium abscessus in vitro and in vivo.

ABSTRACT:

Background

Mycobacterium abscessus causes chronic pulmonary infections. Owing to its resistance to most classes of antibiotics, treatment is complex and cure rates are only 45%. Tigecycline is active against M. abscessus, but severe toxicity and the need for IV administration limit its use.

Objectives

To assess the potential of inhaled tigecycline as a treatment for M. abscessus pulmonary disease, by measuring its efficacy in a mouse model of chronic M. abscessus pulmonary disease, establishing the intracellular activity of tigecycline against M. abscessus in human macrophages and measuring the activity of tigecycline in the sputum of cystic fibrosis patients.

Methods

We infected GM-CSF knockout mice with M. abscessus by intrapulmonary aerosol. Infected mice were treated with tigecycline in 0.25, 1.25 and 2.5?mg doses, by inhalation, or untreated, for 28?days. Tigecycline was added to human peripheral blood-derived macrophages infected with M. abscessus to assess its intracellular activity. We performed a time-kill kinetics experiment of tigecycline against M. abscessus with and without sputum of cystic fibrosis patients.

Results

Inhaled tigecycline proved highly effective against M. abscessus in GM-CSF knockout mice. The effect was dose dependent. Tigecycline showed potent activity against M. abscessus in macrophages and retained most of its activity in the presence of sputum of cystic fibrosis patients.

Conclusions

Inhaled tigecycline may represent a viable treatment option for M. abscessus pulmonary disease, where treatment outcomes are currently very poor. A stable and safe formulation is required to proceed to further pharmacodynamic studies and ultimately clinical trials.

SUBMITTER: Pearce C

PROVIDER: S-EPMC7778363 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Publications

Inhaled tigecycline is effective against Mycobacterium abscessus in vitro and in vivo.

Pearce Camron C Ruth Mike M MM Pennings Lian J LJ Wertheim Heiman F L HFL Walz Amanda A Hoefsloot Wouter W Ruesen Carolien C Muñoz Gutiérrez Juan J Gonzalez-Juarrero Mercedes M van Ingen Jakko J

The Journal of antimicrobial chemotherapy 20200701 7

<h4>Background</h4>Mycobacterium abscessus causes chronic pulmonary infections. Owing to its resistance to most classes of antibiotics, treatment is complex and cure rates are only 45%. Tigecycline is active against M. abscessus, but severe toxicity and the need for IV administration limit its use.<h4>Objectives</h4>To assess the potential of inhaled tigecycline as a treatment for M. abscessus pulmonary disease, by measuring its efficacy in a mouse model of chronic M. abscessus pulmonary disease ...[more]

PMID: 32294173

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Project description:The aminobenzimidazole SPR719 targets DNA gyrase in Mycobacterium tuberculosis. The molecule acts as inhibitor of the enzyme's ATPase located on the Gyrase B subunit of the tetrameric Gyrase A2B2 protein. SPR719 is also active against non-tuberculous mycobacteria (NTM) and recently entered clinical development for lung disease caused by these bacteria. Resistance against SPR719 in NTM has not been characterized. Here, we determined spontaneous in vitro resistance frequencies in single step resistance development studies, MICs of resistant strains, and resistance associated DNA sequence polymorphisms in two major NTM pathogens Mycobacterium avium and Mycobacterium abscessus. A low-frequency resistance (10-8/CFU) was associated with missense mutations in the ATPase domain of the Gyrase B subunit in both bacteria, consistent with inhibition of DNA gyrase as the mechanism of action of SPR719 against NTM. For M. abscessus, but not for M. avium, a second, high-frequency (10-6/CFU) resistance mechanism was observed. High-frequency SPR719 resistance was associated with frameshift mutations in the transcriptional repressor MAB_4384 previously shown to regulate expression of the drug efflux pump system MmpS5/MmpL5. Our results confirm DNA gyrase as target of SPR719 in NTM and reveal differential resistance development in the two NTM species, with M. abscessus displaying high-frequency indirect resistance possibly involving drug efflux. IMPORTANCE Clinical emergence of resistance to new antibiotics affects their utility. Characterization of in vitro resistance is a first step in the profiling of resistance properties of novel drug candidates. Here, we characterized in vitro resistance against SPR719, a drug candidate for the treatment of lung disease caused by non-tuberculous mycobacteria (NTM). The identified resistance associated mutations and the observed differential resistance behavior of the two characterized NTM species provide a basis for follow-up studies of resistance in vivo to further inform clinical development of SPR719.

Project description:As a consequence of a growing population of immunocompromised individuals, including transplant recipients and cystic fibrosis patients, there has been a dramatic increase in chronic infections caused by Mycobacterium abscessus complex (MABC) strains that are usually recalcitrant to effective antibiotic therapy. The recent rise of macrolide resistance in MABC has further complicated this clinical dilemma, dramatizing the need for novel agents. The repurposing of current antibiotics is one rapid path from discovery to patient care. In this study, we have discovered that dual β-lactams, and specifically the combination of ceftazidime with either ceftaroline or imipenem, are synergistic and have clinically relevant activities, with MIC50s of 0.25 (ceftaroline with 100 µg/ml ceftazidime) and 0.5 µg/ml (imipenem with 100 µg/ml ceftazidime) against clinical MABC isolates. Similar synergy was observed in time-kill studies against the M. abscessus ATCC 19977 strain using clinically achievable concentrations of either imipenem (4 µg/ml) or ceftaroline (2 µg/ml), as the addition of ceftazidime at concentrations of ≥50 µg/ml showed a persistent bactericidal effect over 5 days. Treatment of THP-1 human macrophages infected with three different M. abscessus clinical isolates supported the in vitro findings, as the combination of 100 µg/ml ceftazidime and 0.125 µg/ml ceftaroline or 100 µg/ml ceftazidime and 0.25 µg/ml imipenem dramatically reduced the CFU counts to near baseline levels of infection. This study's finding that there is synergy between certain β-lactam combinations against M. abscessus infection provides optimism toward identifying an optimum dual β-lactam treatment regimen.IMPORTANCE The emergence of chronic MABC infections among immunocompromised populations and their inherent and acquired resistance to effective antibiotic therapy have created clinical challenges in advancing patients for transplant surgery and treating those with disease. There is an urgent need for new treatment regimens, and the repurposing of existing antibiotics provides a rapid strategy to advance a laboratory finding to patient care. Our recent discoveries that dual β-lactams, specifically the combination of ceftazidime with ceftaroline or ceftazidime with imipenem, have significant in vitro MIC values and kill curve activities and are effective against infected THP-1 human macrophages provide optimism for a dual β-lactam treatment strategy against MABC infections. The unexpected synergistic activities reported in this study create a new path of discovery to repurpose the large family of β-lactam drugs.

Dataset Information

Inhaled tigecycline is effective against Mycobacterium abscessus in vitro and in vivo.

Background

Objectives

Methods

Results

Conclusions

Publications

Inhaled tigecycline is effective against Mycobacterium abscessus in vitro and in vivo.

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