An overview of gram-negative bacteria with difficult-to-treat resistance: definition, prevalence, and treatment options

ABSTRACT

Introduction

Difficult-to-treat resistance (DTR) is a newly proposed resistance phenotype characterized by resistance to all first-line drugs. The emergence of DTR as a new resistance phenotype has significant implications for clinical practice. This new concept has the potential to be widely used instead of traditional phenotypes.

Areas covered

This study carried out a detailed analysis about the definition, application, and evolution of various resistance phenotypes. We collected all the research articles on Gram-negative bacteria with difficult-to-treat resistance (GNB-DTR), analyzed the DTR in each region and each bacterial species. The advantages and doubts of DTR, the dilemma of GNB-DTR infections and the potential therapeutic strategies are summarized in the review.

Expert opinion

Available studies show that the prevalence of GNB-DTR is not optimistic. Unlike traditional resistance phenotypes, DTR is more closely aligned with the clinical treatment perspective and can help with the prompt selection of an appropriate treatment plan. Currently, potential treatment options for GNB-DTR include a number of second-line drugs and novel antibiotics. However, the definition of first-line drugs is inherently dynamic. Therefore, the DTR concept based on first-line drugs needs to be continuously updated and refined, considering the emergence of new antibiotics, resistance characteristics, and pathogen prevalence in different regions.

KEYWORDS:

• Difficult-to-treat resistance
• Gram-negative bacteria
• GNB-DTR
• prevalence
• potential treatment options

Article highlights

• This study carried out a detailed analysis about the definition, application, and evolution of various resistance phenotypes (PDR, XDR, MDR, CR, ECR, FQR, DTR).

• Available studies show that the prevalence of GNB-DTR is not optimistic, particularly in Pseudomonas aeruginosa and Acinetobacter baumannii, with an average proportion of DTR reaching 14.95% and 56.2%, respectively.

• Currently, potential treatment options for GNB-DTR include a number of second-line drugs and novel antibiotics. Colistin/polymyxin B, aminoglycosides and tigecycline have good in vitro activity against GNB-DTR, as their clinical use is limited by their adverse reactions. Cefiderocol, novel β-lactam and β-lactam-β-lactamase inhibitor combinations have been used clinically to successfully cure infections caused by GNB-DTR.

• Several studies have highlighted the correlation between infections caused by antibiotic-resistant bacteria and negative patient outcomes, such as prolonged hospital stays, increased incidence rates, and higher mortality rates. The treatment dilemma of GNB-DTR infection is primarily due to the high level of resistance to first-line drugs, the potential for adverse reactions with second-line drugs, and the limited availability of new antibiotics.

• The advantages of DTR are summarized below. Firstly, compared to traditional resistance phenotypes, such as PDR and XDR, the DTR phenotype is more straightforward and clear-cut. Secondly, infections caused by DTR have a higher mortality rate compared to other single-variety resistance phenotypes. Thirdly, it helps clinicians quickly adopt appropriate empirical treatment regimens and prevent adverse consequences.

• Definition of DTR may become outdated with the introduction of new antibiotics, particularly when it comes to evaluating first-line treatments. First-line drugs for different types of bacteria are constantly changing, which also affects the specific antibiotics involved in DTR.

Declaration of financial/other relationships

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.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Author contributions

JJZ conceived the original idea, formulated the study conception, performed the statistical analysis and drafted first version of the manuscript. BBL searched the literature and sort it out. HZ engaged in extracting the relevant data. LYC performed the judgment of controversy in the process of data extraction. YC contributed to the original idea conception, data interpretation and manuscript revision. All authors reviewed and approved the final manuscript and agreed to be accountable for all aspects of the work.

Additional information

Funding

This work was supported by the National Natural Science Foundations of China [82073894], Cultivation Project of PLA General Hospital for Distinguished Young Scientists [2020-JQPY-004] and New Medicine Clinical Research Fund [4246Z512].