Novel Agents for Drug-Resistant Gram-Negative Infections

Abstract and Introduction

Abstract

Purpose of Review: To review novel antiinfective agents in development for multidrug-resistant (MDR) Gram-negative bacterial infections.

Recent Findings: Four novel agents are in various phases of development (tebipenem, durlobactam-sulbactam, cefepime-taniborbactam, and xeruborbactam). Tebpipenem is an oral carbapenem with a recently completed phase III trial for complicated urinary tract infections while durlobactam-sulbactam represents a potential alternative for drug-resistant Acinetobacter baumannii. Cefepime-taniborbactam possesses in-vitro potency against a range of troubling pathogens and we await further information on a recently completed study on complicated urinary tract infection. Finally, xeruborbactam is an ultrabroad beta-lactamase inhibitor that can be paired with a range of intravenous and oral agents. It exhibits enhanced in-vitro activity against many MDR pathogens, including those resistant to newer, broader spectrum options. Data in humans with xeruborbactam are limited.

Summary: Each of the newer options reviewed possesses a unique range of in-vitro activity against select, challenging pathogens with some narrowly tailored and other broader in activity. Several have both oral and intravenous formulations. Two agents have presented data from recent phase III trials, whereas two are not as advanced in their clinical programs.

Introduction

Severe infections remain associated with significant morbidity and mortality. This is particularly true for infections such as nosocomial pneumonia, sepsis, and complicated urinary tract infections (cUTI). The explosion in antibiotic resistance over the last 2 decades has added the burden of these processes. Pathogens resistant to many antibiotics are now routinely encountered in all types of infections. In the past, organisms such as Staphylococcus aureus represented the key dilemma. Antimicrobial resistance in Gram-negative bacteria (GNB), though, now has supplanted Gram-positive pathogens as the central dilemma.

Multiple surveys illustrate the growing challenge. For example, a recent analysis indicated that more than 60% of cases of nosocomial pneumonia result from one of several GNB.^[1,2] The important GNB pathogens include Enterobacterales spp. (e.g., Klebsiella pneumoniae Escherichia coli), Pseudomonas aeruginosa, and Acinetobacter baumannii. In addition, many of these causative agents exhibit resistance to multiple antiinfectives and thus are defined as multidrug-resistant (MDR). Hence, the clinician's challenge is even that much more acute as she has few to no alternatives to combat such infections. Predictably, physicians have responded to this evolution in microbiology by reflexively prescribing agents with broader spectrums of in-vitro activity. This behavior arises from an effort to ensure the patient receives initially appropriate antibiotic therapy – a key determinant of outcome in multiple infections.^[3] This approach to antibiotic use, unfortunately, serves to foster resistance.

Issues with resistance are most pronounced in the ICU. The results of the EPIC III survey underscore the conundrum.^[4] In this report including over 8000 patients, GNB predominated. In addition, pneumonia represented the most common infectious process. The investigators described substantial increases in MDR bacteria. For instance, more than 30% of infections due to GNB were caused by MDR organisms.^[4]

Given the evolving burden of MDR infections, efforts have begun to emphasize the development of novel therapies to combat these bacteria. In one sense, there remains a race between the ability of pathogens to evolve unique mechanisms of antibiotic resistance and the work of drug developers to create novel options to respond to these changes. Specifically, four novel agents are in various phases of development – tebipenem, sulbactam-durlobactam, cefepime-taniborbactam, and xeruborbactam. Several of these drugs have undergone rigorous phase III trials, whereas others are in earlier phases of study that address in-vitro activity and general safety. Each of these four agents has unique attributes that might make them useful to clinicians in their efforts to treat resistant infections. In addition, all are broadly designed to address several types of MDR organisms, whereas some are intended to combat specific pathogens. To appreciate the potential role of these treatments in development, one needs a comprehensive understanding not only of their in-vitro activity and mechanisms of action but also of their pharmacokinetic and pharmacodynamic properties. Moreover, readers need to comprehend the clinical trial data documenting their efficacy.