IDSA 2024 Guidance: Managing Antimicrobial-Resistant Gram-Negative Infections

The Infectious Diseases Society of America (IDSA) has released updated guidance for managing antimicrobial-resistant (AMR) infections, including those caused by extended-spectrum β-lactamase-producing Enterobacterales (ESBL-E), AmpC β-lactamase-producing Enterobacterales (AmpC-E), carbapenem-resistant Enterobacterales (CRE), difficult-to-treat Pseudomonas aeruginosa (DTR P. aeruginosa), carbapenem-resistant Acinetobacter baumannii (CRAB), and Stenotrophomonas maltophilia. This update supersedes previous versions of the guidance.

The document outlines preferred and alternative treatment approaches based on the causative organism and antibiotic susceptibility results. It covers strategies for empiric treatment, transitioning to oral therapy, therapy duration, and other management considerations. The guidance is applicable to both adults and pediatric populations, but antibiotic dosages are provided only for adults.

In an exclusive interview with Contagion^®, 2 panel members Julie Ann Justo, PharmD, MS, FIDSA, BCPS, and Emily Heil, PharmD, MS, discussed the IDSA 2024 guidance on treating antimicrobial-resistant gram-negative infections.

The panel consisted of 6 infectious diseases specialists who developed questions concerning the treatment of infections caused by ESBL-E, AmpC-E, CRE, DTR P. aeruginosa, CRAB, and S. maltophilia. This document addresses the treatment of AMR infections within the United States, considering variations in AMR epidemiology and global availability of specific anti-infectives.

Justo, a clinical pharmacist lead in infectious diseases at Dartmouth Hitchcock Medical Center and who serves as codirector of the antimicrobial stewardship program, said that “the 2024 guidance update represents Version 4 of this document, highlighting the rapidly evolving field of antimicrobial-resistant gram-negative infections and the need for frequent updates due to changes in epidemiology and available drug products.”

Heil, a professor at the University of Maryland School of Pharmacy in Baltimore, Maryland, also works as an infectious diseases clinical pharmacy specialist at the University of Maryland Medical Center. “It’s important to clarify that this is a guidance document, not a formal guideline. Unlike traditional guidelines that follow GRADE methodology and involve methodologists, this guidance aims to provide timely updates with less formal processes due to the rapidly changing data," she said.

Both experts discuss how the guidance addresses the evolving landscape of antimicrobial resistance and emerging resistance mechanisms. “Frequent literature searches and staying connected with the field through conferences and industry updates help us incorporate new data as it emerges. While new developments may not be in the current document, they will be included in the next iteration," Heil noted.

Justo followed up with an example that one of the major changes from Version 3 to Version 4: the recognition of evolving epidemiologic trends, specifically the increasing incidence of metallo-beta-lactamases among carbapenem-resistant Enterobacterales.

Notable Updates from the 2023 IDSA AMR Guidance

ESBL-E:

• Ceftolozane-tazobactam: Likely effective against ESBL-E, recommended for severe cases like DTR Pseudomonas or polymicrobial infections.
• Amoxicillin-clavulanic acid: Not preferred for uncomplicated ESBL cystitis but may be used if other oral options aren’t suitable; patients should be warned about the risk of recurrent infections.
• Fosfomycin: Not recommended for pyelonephritis and complicated urinary tract infections (cUTIs), though recent data questions the benefits of additional oral doses.
• Piperacillin-tazobactam: Not recommended for pyelonephritis and cUTIs; if used and the patient improves, continuing it may carry a higher risk of treatment failure.

AmpC-E:

• Moderate risk: Previously termed “moderate to high risk” for AmpC production.
• Intrinsic resistance: Certain antibiotics are ineffective because of basal AmpC β-lactamases, even without increased AmpC production.
• Cefepime: The previous recommendation against cefepime for certain bacteria with specific MIC levels has been removed because of new data.

CRE:

• Metallo-beta-lactamases (MBL): Rising CRE strains producing MBL in the US.
• New CLSI method: For testing ceftazidime-avibactam and aztreonam against MBL-producing bacteria.
• Dosing: Updated dosing for ceftazidime-avibactam with aztreonam is recommended every 8 hours.

DTR Pseudomonas aeruginosa:

• High-dose extended-infusion therapy: Suggested for P aeruginosa resistant to all carbapenems but susceptible to other β-lactams (like cefepime), without repeated susceptibility testing.
• New guidance: Discusses differences in β-lactam activity against DTR Pseudomonas and regional resistance mechanisms.
• Once-daily tobramycin or amikacin: Recommended for pyelonephritis or cUTI caused by DTR Pseudomonas because of their long activity in the kidneys.

CRAB:

• Sulbactam-durlobactam: Preferred treatment for CRAB infections, in combination with meropenem or imipenem-cilastatin.
• High-dose ampicillin-sulbactam: An alternative in combination with at least one other agent, if sulbactam-durlobactam is unavailable; new dose recommendation is 27 grams of ampicillin-sulbactam (18 grams ampicillin, 9 grams sulbactam) daily.

S maltophilia:

• Preferred treatments: Listed in order: cefiderocol (with a second agent initially), ceftazidime-avibactam and aztreonam, minocycline (with a second agent), TMP-SMX (with a second agent), or levofloxacin (with a second agent).
• New CLSI method: For testing ceftazidime-avibactam and aztreonam activity against S maltophilia.
• Tigecycline: Removed from combination therapy recommendations.
• New CLSI guidance: Advises against testing ceftazidime for S maltophilia infections.

Challenges

The panel faced challenges when developing treatment recommendations for resistant pathogens. Justo highlighted the issue of insufficient clinical data for certain pathogens, such as S maltophilia. “This pathogen is difficult to study because it is often unclear whether it is a colonizer or an infecting pathogen," she said. "This uncertainty complicates systematic research and the development of meaningful treatment recommendations. Our panel worked to combine basic science literature with the available clinical outcomes data to create rational therapeutic recommendations. However, we acknowledge the gaps in data and hope that this will encourage further research in these areas.”

Heil addressed the challenges related to implementing sulbactam-durlobactam for the treatment of carbapenem-resistant Acinetobacter baumannii, acknowledging that the “drug is new, expensive, and may not be readily available in all hospitals. Additionally, there are logistical issues like setting up microbiology labs to test for susceptibilities. Balancing the clinical benefits of the new drug with practical considerations of drug access and implementation was complex. It’s important to make recommendations that are not only evidence-based but also practical for real-world application, considering all logistical and access issues.”

Key considerations for clinicians

When transitioning from empirical to targeted therapy based on antibiotic susceptibility results, they emphasized the need to understand microbiologic testing and optimize dosage regimens. Heil stated, "Knowing what tests are performed and how results are interpreted is essential. Understanding breakpoints and the site of infection, whether the drug reaches that site in adequate concentrations, is also important for choosing the most effective agent.”

“Version Four has updated the dosing table and susceptibility breakpoints for various gram-negative pathogens. The updated version includes practical adjustments, such as extended infusions for beta-lactams and streamlined regimens for complex treatments,” Justo said. She provides the example that the dosing regimen for ceftazidime-avibactam plus aztreonam has been simplified to allow simultaneous administration every eight hours, which improves logistical feasibility.

Overall, given the rapidly evolving nature of AMR, consulting with an infectious diseases specialist is recommended for optimal management of these infections. This document is current as of December 31, 2023, and will be updated periodically.

Reference

Infectious Diseases Society of America. IDSA 2024 Guidance on the Treatment of Antimicrobial Resistant Gram-Negative Infections. Published Clinical Infectious Diseases July 12, 2024. Accessed August 7, 2024. https://www.idsociety.org/practice-guideline/amr-guidance/