Challenges in Managing Multidrug-Resistant Gram-Negative Infections

Abstract

Introduction

Multidrug-resistant Gram-negative infections pose significant challenges, particularly in developing countries where carbapenem-resistant organisms, such as Enterobacterales, Acinetobacter baumannii, and Pseudomonas aeruginosa (CRE, CRAB, and CRPA), are prevalent. The World Health Organization has highlighted these as priority pathogens due to their high rates of resistance and the urgent need for new antibiotics to treat them. This talk will address the challenges in managing these infections and explore current treatment options through instructive case scenarios and literature reviews.

Methods

We performed a comprehensive review of current literature on the global epidemiology and management of carbapenem-resistant infections, particularly with polymyxin-based therapies and newer beta-lactam/beta-lactamase inhibitor (BL/BLI) combinations. The molecular mechanisms responsible for carbapenem-resistant infections, the uniqueness of different pathogens, and the distribution of resistance across geographical locations were examined. Clinical outcomes from recent studies and trials were analyzed to assess the effectiveness and limitations of available treatment options to help clinicians choose appropriate treatment strategies.

Results

In 2019, there were 4.95 million deaths related to global antimicrobial resistance (AMR), and it was projected that by 2050, there will be 10 million annual deaths attributable to AMR. Developing nations experience a disproportionately higher burden of AMR-related deaths. In India alone, 297,000 deaths in 2019 were attributable to AMR, with 1,042,500 deaths associated with it. Most AMR-associated deaths were due to three priority pathogens: Escherichia coli (152,700 deaths), Klebsiella pneumoniae (123,200 deaths), and Acinetobacter baumannii (103,500 deaths). ESBL resistance among Enterobacterales was around 80%, with carbapenem resistance rates of 40-50% and 70-80% among Klebsiella and Acinetobacter strains, respectively. Although treatment with Polymyxin-based therapies is a mainstay in developing countries, it presents significant challenges due to dosing issues, poor drug concentration, and nephrotoxicity. Newer BL/BLIs, such as ceftazidime-avibactam and meropenem-vaborbactam, are promising alternatives but come with poor availability and high costs. They are also less effective against metallo-beta-lactamase-producing organisms like NDM, which are common in South and Southeast Asia.

Discussion

The management of carbapenem-resistant infections varies significantly between developed and developing countries. Despite their limitations, polymyxin-based therapies are commonly prescribed in developing countries due to their accessibility and low cost. Newer BL/BLIs show promise but have limitations, such as cost, availability and efficacy. The efficacy of these treatment options is further complicated by the presence of additional resistance mechanisms, such as PBP3 inserts in CRE and MBLs in CRPA and CRAB.

Conclusion

The fight against multidrug-resistant Gram-negative infections requires a multifaceted approach. Advancements in antimicrobials and BL/BLI combinations are constrained by regional resistance patterns and economic factors. Addressing antimicrobial resistance in developing countries necessitates responsible prescription of antibiotics, stringent antimicrobial stewardship programs, regulated antibiotic usage, robust infection control practices, and the development of new agents to curb the spread of resistance.