Efficacy and appropriateness of novel antibiotics in response to antimicrobial-resistant gram-negative bacteria in patients with sepsis in the ICU

ABSTRACT

Introduction

There is an ever-increasing range of antibiotic-resistant pathogens that have led to higher community-acquired infections, and substantial mortality rates in critically ill patients.

Areas covered

We have critically appraised available evidence through a structured literature review, investigating effective empiric antibiotic administration and appropriateness on outcomes of critically ill patients with an increased risk of developing resistant pathogens. The use of new antibiotics should be determined based on relevant knowledge of their spectrum and properties to provide effective mode of action for critically ill patients.

Expert Opinion

Restricting severely ill patients access to new broad-spectrum empirical drugs is not the answer. Rather there should be a focus on identifying host response to infection to differentiate between colonization or contamination and true infection, and the sensitivity to antibiotics used in the intensive care unit (ICU). Management relies on adequate antibiotic administration, the ability to monitor response, and facilitate the cessation of antibiotic treatment. The major determinant of patient success in a patient with a severe infection is the ‘right’ antibiotic or complementary course of treatment. As an overarching criterion, the following three appropriate “Ds” should be considered: Dosing, Duration, and De-escalation to empirically assess the right antibiotic optimal antimicrobial selection.

KEYWORDS:

• Critically ill patients
• sepsis
• septic shock
• broad-spectrum antibiotics
• antimicrobial-resistant gram-negative bacteria
• novel mode of action
• multidrug resistance in ICU
• cross-resistance
• pharmacodynamic targets

Article highlights

• There are promising new agents being developed and close to approval in clinical trials. However, there is still a need for developing antibiotics against gram-negative strains including those that harbor metallo-β-lactamase (MBL).

• Trials designed for equivalence are a problem considering most are modifications of older agents, or with new β-lactamase inhibitors.

• High potential for rapid evolution of resistance is a result of single mutation in a target determining gene. This warrants the need for a shift in focus from single molecular target agent development to new chemical scaffolds or binding sites that can be targeted alongside a de-escalation approach based on empirical targeted treatment, sensitivity to antibiotics, and host response to infection.

• Superiority to current regimens for carbapenem-resistant Enterobacterales (CRE) infection have not been completely assessed. There is a need for randomized controlled trials (RCTs) in settings other than complicated intra-abdominal infections (cIAI), and complicated urinary tract infections (cUTI). Assessment on current regimens for S. aureus bloodstream infections, ventilator associated pneumonia (VAP) and other multidrug-resistant infections is warranted.

• High costs may limit access to new agents in resource-poor-settings. There is a need to evaluate their respective potential at individual institutions based on appreciation of local problem pathogens.

• Clinical assessment in intensive care units can be misleading because inflammation and infection have been shown to share similar features. Future tools should help identify the bacteria early, measure the size of the inoculum, and differentiate inflammation and infection to incorporate further biomarkers with a focus on their utility in clinical practice.

• Optimal loading dose antibiotic duration regimen should be promptly narrowed or discontinued based on culture, susceptibility profile results, organ-specific infection target attainment, and on clinical stability.

Declaration of interest

Martin-Loeches discloses providing lectures for Gilead, Merck, Pfizer, as well as advisory board membership for Merck. 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.

Author contributions

IML developed the clinical formalism and AG developed the focus and search strategy. AG provided substantial contributions to the design of the critical review. AG conducted an appraisal of each research study and clinical trial to distinguish between efficacy, efficiency and effectiveness in several novel antibiotics used to treat critically ill patients in ICU more tailored to patients with Sepsis/Septic shock. AG focused on alternative dosing strategies for multidrug resistant (MDR) and difficult-to-treat resistant (DTR) pathogens in ICU. IML conducted multiple revisions and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part on the scientific appraisal are appropriately investigated.