Perspectives on synthetic pharmacotherapy for the treatment of nosocomial pneumonia

ABSTRACT

Introduction: Nosocomial pneumonia is the second most common infection in hospital settings, resulting in substantial increases in morbidity, mortality, and length of hospital stay. The rapid increase in resistance of nosocomial pathogens to many antibiotics and the high dissemination of resistance genes highlight the need for innovative approaches to combat difficult-to-treat nosocomial respiratory infections.

Areas covered: This review summarizes the synthetic antimicrobials that are currently in development for the treatment of nosocomial pneumonia, focusing on antibiotics in the final phases of clinical development and on the strategies employed by novel synthetic antimicrobial peptides.

Expert opinion: Several novel synthetic antimicrobials are currently in the pipeline, and it appears that new antimicrobial peptides or mimetics will soon be made available, expanding the opportunities to treat nosocomial pneumonia. However, the approval process for use in the treatment of nosocomial pneumonia is arduous. Given that significant investments by pharmaceutical companies have ended in failure to obtain the approval of regulatory agencies, novel platforms for antimicrobial discovery are needed. The identification of new and fully synthetic chemical structures with activity against nosocomial pathogens needs to be followed by preclinical studies in large animals and by pharmacokinetic and pharmacodynamic studies in specific critically ill populations to assess lung penetration.

KEYWORDS:

• Synthetic antimicrobials
• antimicrobial peptides
• host-defense peptide mimetics
• pharmacotherapy
• ventilator-associated pneumonia
• hospital-acquired pneumonia

Article highlights

• Despite improvements in treatment and supportive care, nosocomial pneumonia remains a leading cause of death in hospital settings.

• The development of novel synthetic antimicrobials holds promise for the treatment of multidrug-resistant infections.

• Innovative discovery platforms have the potential to be able to develop thousands of compounds by high-throughput techniques, offering the potential to construct chemical repositories suitable for screening.

• Synthetic antimicrobials for the treatment of hospital-acquired or ventilator-associated pneumonia are still in early development. Notable exceptions to this are the oxazolidinones and quinolones, while compounds such as tedizolid and iclaprim are in the final phases of development.

• Antimicrobial peptides or mimetics have several attractive properties that make them a promising therapeutic option for treating multidrug-resistant infections. Of these, murepavadin (POL7080) is probably best positioned to reach the market for the treatment of hospital-acquired or ventilator-associated pneumonia due to P. aeruginosa.

This box summarizes the key points contained in the article.

Declaration of interest

A Torres has received grants from MedImmune, Cubist, Bayer, Theravance, and from Polyphor. Furthermore, he has received personal fees for advisory board participation from Bayer, Roche, The Medicines Company, Curetis. He has also received personal fees for rapid molecular tests from Curetis, as well as grants as the Principle Investigator of a Phase III study on Cefatzidime/Avibactam for HAP/VAP, during the conduct of the study from AstraZeneca. He has received personal fees from GlaxoSmithKline for an educational symposium (Siglo XXI), from Pfizer for a sponsored vaccine symposium, from AstraZeneca for speaking at symposia on ceftaroline and from the Biotest Advisory Board for Enriched IgM for severe CAP, outside of the submitted work. 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.

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Funding

This manuscript has not been funded.