Host-directed therapies for antimicrobial resistant respiratory tract infections
Markus Maeurer1, Martin Rao, Alimuddin Zumla
1aDivision of Therapeutic Immunology (TIM), Department of Laboratory Medicine (LABMED), Karolinska Institutet bCentre for Allogeneic Stem Cell Transplantation (CAST), Karolinska University Hospital Huddinge, Stockholm, Sweden cDivision of Infection and Immunity, University College London dNIHR Biomedical Research Centre, University College London Hospitals NHS Foundation Trust, London, UK.
Purpose Of Review:
Antimicrobial-resistant respiratory tract infections (AMR-RTIs) are increasing, presenting important management challenges worldwide. Current management of AMR-RTI patients focuses on pathogen-directed antimicrobial treatment. Overt lung inflammation, parenchymal damage, and ineffective immune activation perpetrate increased patient morbidity and mortality. Immunomodulatory and tissue-regenerative host-directed therapies (HDT) may improve treatment outcomes. HDTs under investigation for improving AMR-RTI treatment outcomes are reviewed.
Recent Findings:
Various HDTs are being developed or evaluated for adjunctive AMR-RTI treatment. α-1 antitrypsin was shown to reduce Pseudomonas aeruginosa burden in the airways of cystic fibrosis patients. Cellular therapy by reinfusing autologous bone marrow-derived MSCs into MDR/XDR-TB patients shows promise, whereas adjunctive T cell-based therapies are considered. Cytotoxic therapy using etoposide, a topoisomerase II-inhibiting anticancer drug extends survival of patients with severe influenza H1N1 infection-induced hemophagocytic lymphohistiocytosis. Two other novel HDT candidates, DAS181 and resveratrol show antiinfluenza effects. Novel kinase inhibitors SB203580 (MAPK-2 antagonist) and LY294002 (phosphoinositide-3 kinases antagonist) exhibit promising anti-MERS-CoV activity. Palivizumab, an anti-RSV monoclonal antibody, effectively prevents RSV infection in high-risk paediatric populations. T-cell therapy is currently considered for adjunctive HDT of azole-resistant pulmonary aspergillosis.
Summary:
Novel HDTs may revolutionize future treatment regimens for AMR-RTIs. Well designed multisite clinical trials are now necessary to accelerate progress.
Insights
Novel host-directed therapies (HDTs) show promise for treating antimicrobial-resistant respiratory tract infections (AMR-RTIs). These treatments target host responses to improve outcomes beyond traditional pathogen-focused approaches, necessitating further clinical trials.
Area of Science:
- Respiratory Medicine
- Infectious Diseases
- Immunology
Background:
- Antimicrobial-resistant respiratory tract infections (AMR-RTIs) pose a growing global health challenge.
- Current treatments primarily focus on antimicrobials, often failing to address underlying host pathology like inflammation and tissue damage.
- Host-directed therapies (HDTs) offer a complementary strategy by modulating the host response to improve outcomes.
Purpose of the Study:
- To review emerging host-directed therapies (HDTs) under investigation for the treatment of antimicrobial-resistant respiratory tract infections (AMR-RTIs).
- To highlight novel therapeutic approaches that target host immune responses and tissue regeneration.
- To assess the potential of HDTs to improve clinical outcomes in patients with AMR-RTIs.
Main Methods:
- Review of current literature on host-directed therapies for AMR-RTIs.
- Identification and categorization of various investigational HDTs.
- Summary of preclinical and clinical findings for selected HDTs.
Main Results:
- Several HDTs demonstrate potential, including α-1 antitrypsin for Pseudomonas aeruginosa, mesenchymal stem cells (MSCs) for multidrug-resistant tuberculosis (MDR/XDR-TB), and T-cell therapies.
- Anticancer drugs like etoposide show efficacy in severe influenza-induced hemophagocytic lymphohistiocytosis.
- Novel agents like DAS181, resveratrol, kinase inhibitors (SB203580, LY294002), and monoclonal antibodies (Palivizumab) exhibit specific anti-infective or immunomodulatory effects against various respiratory pathogens.
- T-cell therapy is also being explored for azole-resistant pulmonary aspergillosis.
Conclusions:
- Novel HDTs hold significant potential to transform the treatment landscape for AMR-RTIs.
- Further well-designed, multisite clinical trials are crucial to validate the efficacy and safety of these promising therapies.
- A shift towards integrated treatment strategies combining pathogen-directed and host-directed approaches may be necessary for optimal patient management.
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