title: Host-directed therapies for antimicrobial resistant respiratory tract infections.
abstract: OBJECTIVE
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  Novel HDTs may revolutionize future treatment regimens for AMR-RTIs. Well designed multisite clinical trials are now necessary to accelerate progress.
authors.affiliation: aDivision 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.
authors.forename: Markus
authors.initials: M
authors.lastname: Maeurer
authors.forename: Martin
authors.initials: M
authors.lastname: Rao
authors.forename: Alimuddin
authors.initials: A
authors.lastname: Zumla
mesh_terms: D000890:Anti-Infective Agents / Q000627:therapeutic use*; D003550:Cystic Fibrosis; D006801:Humans; D012141:Respiratory Tract Infections / Q000628:therapy*; D016896:Treatment Outcome
chemical_list: D000890:Anti-Infective Agents