Novel investigational treatments for ventilator-associated pneumonia and critically ill patients in the intensive care unit

ABSTRACT

Introduction

Ventilator-associated pneumonia (VAP) is common; its prevalence has been highlighted by the Covid-19 pandemic. Even young patients can suffer severe nosocomial infection and prolonged mechanical ventilation. Multidrug-resistant bacteria can spread alarmingly fast around the globe and new antimicrobials are struggling to keep pace; hence physicians must stay abreast of new developments in the treatment of nosocomial pneumonia and VAP.

Areas Covered

This narrative review examines novel antimicrobial investigational drugs and their implementation in the ICU setting for VAP. This paper highlights novel approaches such as monoclonal antibody treatments for P. aeruginosa and S. aureus and phage antibiotic synthesis. This paper also examines mechanisms of resistance in Gram-negative bacteria, virulence factors, and inhaled antibiotics and questions what may be on the horizon in terms of emerging treatment strategies.

Expert opinion

The postantibiotic era is rapidly approaching, and the need for personalized medicine, point-of-care microbial sensitivity testing, and development of biomarkers for severe infections is clear. Results from emerging and new antibiotics are encouraging, but infection control measures and de-escalation protocols must be employed to prolong their usefulness in critical illness.

KEYWORDS:

• Ventilator-acquired pneumonia
• nosocomial pneumonia
• critically ill patients
• novel antibiotics/antimicrobials
• inhaled antibiotics
• monoclonal antibodies
• phage

Article highlights

• More than 60 years after the invention of the metered-dose inhaler, we still cannot confidently assess and predict what happens to an inhaled aerosol particle after deposition in the lung, as demonstrated by the INHALE trial. The development of new technology will open new avenues for drug discovery and therapeutic options for patients.

• The potential for use of monoclonal antibodies and vaccines against ventilator pneumonia is an exciting area of study that will hopefully have meaningful outcomes for the sickest patients in hospitals.

• Promising results from the TANGO II trial, demonstrating increased clinical cure and reduced mortality in patients treated for VAP with meropenem/vaborbactam versus best available therapy (BAT).

• A large double-blind randomized control trial (RCT) in critically ill patients with VAP showed Ceftobiprole to be a safe and effective alternative to ceftazidime/linezolid.

• CREDIBLE-CR, a multicenter RCT, showed cefiderocol to be noninferior to BAT in hospital pneumonia and VAP.

• The rediscovery of phage and its potential in phage-antibiotic synergy will revolutionize the treatment of nosocomial pneumonia in the future, this is another encouraging field of ongoing study.

• Ceftobiprole is a potential candidate in combination therapy with daptomycin against a range of gram positive and methicillin-resistant Staphylococcus Aureus (MRSA) related infections. More research is needed in critically ill patients to establish efficacious dosing regimens.

• Success relies on the availability and implementation of rapid sensitivity testing so that we can quickly treat patients with single agent antibiotic regimens that have optimum activity against the agent of choice.

• The absence of clinically useful biomarkers that identify respiratory infection in mechanically ventilated patients and that can predict the severity of such infections is underpinned by our fundamental ignorance of patient immune and inflammation response in this area of medicine. Further treatment dosing regimens and drug delivery systems are warranted.

This box summarizes key points contained in the article.

Declaration of interest

The authors have no 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This paper was not funded.