Since late 2004, 7 novel antibiotics with activity against ESBL-E, CRE, and/or DTR P aeruginosa have been approved.
Antimicrobial-resistant (AMR) bacteria pose grave threats to global public health. In the United States, AMR organisms are estimated to cause an estimated 2.8 million infections per year, resulting in more than 35,000 deaths.1
Infections caused by gram-negative bacteria (GNB), like extended-spectrum β-lactamase–producing Enterobacterales (ESBL-E) or carbapenem-resistant Enterobacterales (CRE), and difficult-to-treat resistance (DTR) non-lactose fermenters, such as Pseudomonas aeruginosa, are therapeutic challenges. Controversies and uncertainties about the roles of older, broad-spectrum agents in the treatment of ESBL-E infections persist, despite the failure of piperacillin-tazobactam to demonstrate noninferiority compared with meropenem in the landmark MERINO trial, which compared the treatments in patients with bacteremia caused by third-generation cephalosporin-resistant Enterobacterales.2
Since late 2014, 7 novel antibiotics with activity against ESBL-E, CRE, and/or DTR P aeruginosa have been approved by the United States Food and Drug Administration: ceftazidime-avibactam (Avycaz), ceftolozane-tazobactam (Zerbaxa), plazomicin (Zemdri), meropenem-vaborbactam (Vabomere), imipenem-cilastatin-relebactam (Recarbrio), cefiderocol (Fetroja), and eravacycline (Xerava).3 Others are poised to follow.
While these agents offer advantages in effectiveness and safety over colistin or polymyxin B, and the long-standing, last-resort antibiotics against CRE or DTR P aeruginosa infections, their uptake into clinical practice has been slow. Moreover, there is considerable confusion among clinicians where specific drugs fit within therapeutic hierarchies.
In parallel with the development of new antibiotics, there have been advances in defining AMR GNB epidemiology. Widespread implementation of rapid and/or molecular diagnostics allow clinicians to identify AMR organisms and characterize resistance mechanisms in real time. Clinical application of molecular platforms and laboratory-based genomic data (such as those generated in the CRACKLE project)4 have demonstrated that CRE in the US is not synonymous with Klebsiella pneumoniae carbapenemase (KPC) production. Indeed, it is clear that CRE are due to a variety of non-KPC mechanisms, including production of metallo-β-lactamases (such as New Delhi metallo-β-lactamase) or porin mutations combined with non-carbapenemase β-lactamase production.
Molecular data are not simply of academic interest, as many new antibiotics are active against strains expressing particular resistance determinants. Therefore, optimal treatment decisions against CRE and other AMR GNB infections require clinicians to be familiar with local epidemiology and resistance mechanisms.
The Infectious Diseases Society of America (IDSA) identified the development and dissemination of timely practice recommendations as a top initiative in its 2019 Strategic Plan.5 The just-released IDSA Guidance on the Treatment of Antimicrobial Resistant Gram-Negative Infections offers practical recommendations for antibiotic management of ESBL-E, CRE, and DTR P aeruginosa infections.6 In the Strategic Plan, IDSA acknowledged that traditional timelines used to generate new or updated clinical practice guidelines limited the ability to address rapidly evolving topics like antimicrobial resistance. IDSA endorsed developing more narrowly focused guidance documents for the treatment of specific, complex infectious processes based on critical review of published data and expert opinion, rather than formal GRADE (Grading of Recommendations Assessment, Development, and Evaluation) criteria. A panel of 5 physicians and 1 pharmacist with clinical and research expertise in the treatment of patients with AMR GNB infections was assembled and given the latitude to identify key problem areas that are addressed in the initial document.
The panel held an initial meeting in March 2020, at which time the 3 pathogen groups above were chosen. Other pathogens were discussed, including AmpC-producing Enterobacterales, carbapenem-resistant (CR) Acinetobacter baumannii, and Stenotrophomonas maltophilia, but were left to subsequent iterations to facilitate timely completion of the initial publication of the first guideline. The panel was split into 3 groups of 2 members each to draft guidance for each of the 3 pathogen groups; recommendations made in the final document were discussed among the entire group over a series of subsequent meetings.
As with any guidance document, opinions differed; however, the panel came to a consensus over each recommendation. The final document addresses 18 important clinical questions and includes 4 summary tables, one of which includes recommended antimicrobial dosing for each recommended agent. As the guidance was intended to be an easily accessible summary, an extensive review of the evidence and detailed rationale were not included for each recommendation. Rather, the panelists intend to provide this additional information as complementary published reviews.
There are several key recommendations in the guidance that should be specifically mentioned. First and foremost, the polymyxins (colistin and polymyxin B) are not recommended for treating any infections by the various pathogens (with one exception) as long as one of the novel β-lactam/β-lactamase inhibitor combinations remains active. Simply put, nearly any alternative is preferred. The sole exception to this is DTR P aeruginosa infections in which cefiderocol is the only active β-lactam. Results from the recently published CREDIBLE-CR trial7 demonstrated an unexplained mortality imbalance favoring primarily polymyxin-based combination therapy over cefiderocol among patients treated for CR GNB infections, including those caused by DTR P aeruginosa. For CRE infections, including those caused by metallo-β-lactamase–producing Enterobacterales, other new agents almost invariably are available and preferred over polymyxin-based therapy.
Second, carbapenem-based therapy (rather than piperacillin-tazobactam) is recommended for the treatment of most infections caused by ESBL-E, including pyelonephritis. The consensus of the panel was that the mortality benefit for carbapenems observed in the MERINO trial is compelling, even when viewed in the light of contradictory observational data. While the data are less clear for pyelonephritis, the panel felt that the hypothetical stewardship considerations (eg, less selective pressure for CR organisms) did not outweigh the potential risks of therapeutic failure. Therefore, the panel determined that it could not recommend piperacillin-tazobactam for the treatment of pyelonephritis caused by ESBL-producing organisms.
Lastly, active β-lactam monotherapy is recommended for the treatment of most multidrug-resistant GNB infections. Observational data for CRE and DTR P aeruginosa infections prior to the advent of the novel β-lactam/β-lactamase inhibitors suggested a benefit with combination therapy with several suboptimal and/or inactive antibiotics, but both observational and randomized trial data for the new agents support the use of monotherapy. This recommendation should not be taken to preclude the use of combination therapy in appropriate situations (eg, polymicrobial infections, medically complex infections where prolonged or indefinite therapy may be likely).
IDSA Guidance on the Treatment of Antimicrobial Resistant Gram-Negative Infections is intended to be a living document. The panel will review the recommendations at least quarterly for revisions, with updates issued as needed based on new evidence. When evidence reaches a threshold where GRADE-based recommendations become reasonable, the panel will convert the document to such a framework. Additionally, the panel will expand the scope of the document to address AMR GNB infections not included in the first iteration.
As a final note, the panel also welcomes comments. The panel is fully vested in adapting recommendations (or providing detailed rationales when not adapted) as outside opinions are voiced and evidence is presented.
Samuel L. Aitken, PharmD, MPH, is a clinical pharmacy specialist, Infectious Diseases, Division of Pharmacy at the University of Texas MD Anderson Cancer Center, Houston, TX
Cornelius J. Clancy, MD, is infectious diseases associate chief at the University of Pittsburgh and chief of the Infectious Diseases Section, VA Pittsburgh Health System.