Enhancement of lung levels of antibiotics by ambroxol and bromhexine

ABSTRACT

Introduction: Major unmet needs remain for improved antibiotic treatment in lung infections. While development of new antibiotics is needed to overcome resistance, other approaches to optimize therapy using existing agents are also attractive. Ambroxol induces lung autophagy at human-relevant doses and improves lung levels of several approved antibiotics.

Areas covered: This review discusses preclinical and clinical studies of the effects of ambroxol (and its prodrug precursor bromhexine) co-treatment upon levels of antibiotics in lung tissue, sputum, and bronchoalveolar lavage fluid.

Expert opinion: Ambroxol co-treatment is associated with significant increases in lung tissue and airway surface fluid levels of a range of antibiotics including beta lactams, glycopeptides, macrolides, nitrofurans, and rifamycins. In most cases, the increased levels are only modest and are insufficient to overcome high-level resistance against that same antibiotic class, and so co-treatment with ambroxol is unlikely to alter clinical outcomes. Additionally, for most antibiotics there is no evidence that outcomes in non-resistant disease are improved by higher drug levels, and there is limited efficacy of co-treatment of antibiotics with ambroxol for most pathogens. The two cases where ambroxol may improve therapy are rifampin-sensitive tuberculosis and non-tuberculous mycobacterial infection, and vancomycin sensitive methicillin resistant Staphylococcus aureus pneumonia.

KEYWORDS:

• Lung pharmacokinetics
• antibiotic resistance
• autophagy

Article highlights

• Ambroxol and bromhexine increase lung levels of a wide range of antibiotics in both preclinical and clinical studies.

• Clinical data shows increases antibiotic levels in sputum and bronchoalveolar lavage fluid while preclinical data shows direct increases in lung tissue.

• The magnitude of ambroxol-induced increases in lung antibiotic levels might in some cases be sufficient to improve outcomes.

Declaration of interest

GS Timmins is co-founder and major stock holder of SpinCeutica Inc. (Santa Fe NM), a company that licenses deuterated ambroxol intellectual property from the University of New Mexico, and is developing this compound for use in treatment of NTM lung disease, and could benefit financially through stock ownership. GS Timmins and V Deretic are co-inventors of the deuterated ambroxol intellectual property, and could also benefit from royalty payments. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was funded by the National Institutes of Health (grant nos. AI122313 & GM121176).