Review of 2023 IDSA Guidelines on AMR Gram-Negative Infections

The Infectious Diseases Society of America (IDSA) has released updated guidelines on the treatment of antimicrobial-resistant (AMR) gram-negative infections. The updated guidance was published in Clinical Infectious Diseases.

The updated guidelines cover preferred and alternative treatment options for 6 AMR gram-negative infections, as follows: 

• Extended-spectrum β-lactamase producing Enterobacterales (ESBL-E);
• AmpC β-lactamase-producing Enterobacterales (AmpC-E);
• Carbapenem-resistant Enterobacterales (CRE);
• Pseudomonas aeruginosa with difficult-to-treat resistance (DTR-P aeruginosa);
• Carbapenem-resistant Acinetobacter baumannii (CRAB); and
• Stenotrophomonas maltophilia. 

A panel of infectious diseases specialists with expertise in managing AMR infections was assembled to suggest preferred and alternative treatment approaches for each pathogen group. They based their suggestions on treatment questions commonly encountered in clinical practice. Each AMR gram-negative infection reviewed has been designated as an urgent or serious threat by the Centers for Disease Control and Prevention (CDC).

ESBL-E Infections

Uncomplicated cystitis 

• Preferred agents include nitrofurantoin and trimethoprim-sulfamethoxazole (TMP-SMX). 
• Alternative agents include ciprofloxacin and levofloxacin.

Piperacillin-tazobactam (TZP) and cefepime are recommended only if initiated as empiric therapy, though the panel advises closely monitoring patients for a clinical response if this approach is selected. 

Pyelonephritis and complicated urinary tract infection (cUTI) 

• Preferred agents include TMP-SMX, ciprofloxacin, and levofloxacin.
• Alternative agents include ertapenem, meropenem, and imipenem-cilastatin.

Infections outside of the urinary tract

• Preferred agents include meropenem, imipenem-cilastatin, and ertapenem.

For patients who respond to preferred agents, a transition to oral agents such as TMP-SMX, ciprofloxacin, and levofloxacin should be considered if susceptibility is observed.

β-lactam-β-lactamase inhibitor combinations such as ceftazidime-avibactam, meropenem-vaborbactam, imipenem-cilastatin-relebactam, and cefiderocol are preferentially reserved for carbapenem-resistant ESBL-E infections outside of the urinary tract.

AmpC-E Infections

Infections caused by E cloacae complex, Klebsiella aerogenes, and Citrobacter freundii with clinically significant ampC production

• Preferred agents include cefepime, if minimum inhibitory concentration is at least 4 mcg/mL.        
• Alternative agents include carbapenems, if susceptibility is demonstrated.

Carbapenem-resistant infections 

• Preferred agents include ceftazidime-avibactam, meropenem-vaborbactam, imipenem-cilastatin-relebactam, and cefiderocol.

Ceftolozane-tazobactam is recommended only for patients at risk for polymicrobial infection.

Uncomplicated cystitis 

• Preferred agents include non-β-lactam therapy such as nitrofurantoin or TMP-SMX. 
• Alternative agents include aminoglycosides.

Other alternatives include TMP-SMX and fluoroquinolones for invasive infections, and ceftriaxone if susceptibility is demonstrated.

CRE Infections

Meropenem- and imipenem-susceptible infections without carbapenemase production or ertapenem susceptibility 

• Preferred agents include extended-infusion meropenem and imipenem-cilastatin. 

Uncomplicated cystitis 

• Preferred agents include nitrofurantoin, TMP-SMX, ciprofloxacin, and levofloxacin. 
• Alternative agents include single-dose aminoglycosides, colistin, ceftazidime-avibactam, meropenem-vaborbactam, imipenem-cilastatin-relebactam, and cefiderocol.

Other alternative agents include oral Fosfomycin for infections in which Escherichia coli is the causative pathogen.

Pyelonephritis and cUTI 

• Preferred agents include TMP-SMX, ciprofloxacin, ceftazidime-avibactam, meropenem-vaborbactam, imipenem-cilastatin-relebactam, and cefiderocol. 
• Alternative agents include aminoglycosides (reserved for patients who can tolerate nephrotoxicity).

The panel also noted that levofloxacin may be considered if susceptibility is demonstrated.

DTR-P aeruginosa Infections

Multidrug-resistant infections susceptible to non-carbapenem β-lactams or carbapenems 

• Preferred agents include TZP, ceftazidime, cefepime, and aztreonam. 

Severe carbapenem-resistant infections

• Preferred agents include ceftolozane-tazobactam, ceftazidime-avibactam, and imipenem-cilastatin-relebactam.

Uncomplicated cystitis, pyelonephritis, and cUTI 

• Preferred agents include ceftolozane-tazobactam, ceftazidime-avibactam, imipenem-cilastatin-relebactam, and cefiderocol.

Infections outside of the urinary tract 

• Preferred agents include ceftolozane-tazobactam, ceftazidime-avibactam, and imipenem-cilastatin-relebactam. 
• Alternative agents include cefiderocol.

CRAB Infections

Although there is no standard antibiotic regimen established for the treatment of CRAB infections, the general approach is high-dose ampicillin-sulbactam in combination with at least 2 other agents, including polymyxin B, minocycline, tigecycline, and cefiderocol.

Combination therapy with cefiderocol should be limited to infections that are refractory to other antibiotics or if alternative agents cannot be tolerated. 

S maltophilia Infections

• Preferred agents include TMP-SMX, minocycline, tigecycline, and cefiderocol.

Combination therapy with ceftazidime-avibactam and aztreonam is recommended for patients with critical illness and those who are nonresponsive to preferred agents.

Looking Ahead 

The IDSA plans to provide additional updates to this guidance annually.

According to the guideline authors, “The field of AMR is dynamic and rapidly evolving, and the treatment of antimicrobial resistant infections will continue to challenge clinicians.”

Disclosure: Multiple study authors declared affiliations with pharmaceutical, biotech, and/or device companies. Please see the original reference for a full list of disclosures.