Time-to-Treat Proves to be Vital in Severely Ill Patients With Gram-Negative Infections


A clinician discusses the ongoing challenges presented with critically ill patients and the timing and scope of antibiotic prescribing practices.

Difficult-to-treat, gram-negative bacterial infections can be especially challenging for clinicians. Issues can include multidrug resistance in critically-ill patients combined with a treatment paradigm in which prescribing practices and timing do not always align with positive outcomes.

“Over and over again, we see people with repeated multiple antibiotic exposures, multiple infections. Even if it started out as maybe a staph infection or was E coli, over time with repeat infections and repeat courses of antibiotics, those [patients] are at greatest risk for a carbapenem-resistant pathogen,” said Tom Lodise, PharmD, PhD, professor at the Albany College of Pharmacy and Health Sciences, and clinical pharmacy specialist at the Stratton VA Medical Center in Albany, New York. “These sort of [case scenarios] is where I think we need to be more aggressive…every day matters in the gram-negative space. We think about antibiotic stewardship—our fundamental pillar is getting it right up front. Despite this, we still find in over half of the patients with an antibiotic resistant gram-negative infection, they do not receive an active drug for the first 48 to 72 hours.”

Addressing Gram-Negative Infections

One antibiotic agent, cefiderocol (Fetroja), manufactured by Shionogi presented new data at this year’s IDWeek in Boston using this antibiotic on gram-negative infections. Specifically, a study demonstrated that the agent was effective in treating these infections in the appropriate patients who received cefiderocol earlier (within 6-20 days of index culture) had lower in-hospital all-cause mortality (IHACM) than those receiving it later (>20 days).1

In the study, cefiderocol was used as monotherapy in 92 (33%) patients, although 253 (92%) had used other gram-negative antibiotics before starting cefiderocol (CFDC). A total of 135 (49.1%) patients started cefiderocol ≤ 5 days of index culture, 108 (39.3%) patients between 6-20 days, and 32 (11.6%) patients > 20 days, according to the investigators.

What You Should Know

Treating gram-negative bacterial infections can be challenging, especially when patients have multidrug resistance and repeat exposure to antibiotics.

Cefiderocol, a cephalosporin antibiotic with a unique mechanism of action, has shown effectiveness in treating gram-negative infections. A study presented at IDWeek demonstrated that patients who received cefiderocol within 6-20 days of the index culture had lower in-hospital all-cause mortality compared to those who received it later.

Cefiderocol received an expanded indication for the treatment of hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia caused by susceptible gram-negative microorganisms.

“Crude overall IHACM was 16.4% (95%CI:12.0%-20.7%): 10.4% for those who started CFDC ≤ 5 days of index culture, 19.4% for 6-20 days, and 31.3% for > 20 days. Crude 14-day and 28-day IHACM from index culture or starting CFDC had the same trend and were lower than overall IHACM,” the investigators wrote.

Lodise says the findings reinforce the importance of time-to-treatment associated with better patient outcomes.

“These findings really highlight what we know; every day matters with our gram-negative infections, and the longer we delay, there's substantial increases in both morbidity and mortality,” Lodise stated.

Expanded Indication

Cefiderocol is a cephalosporin antibiotic with a novel mechanism for penetrating the outer cell membrane of gram-negative pathogens by acting as a siderophore. Back in 2020, the FDA approved a supplemental New Drug Application for cefiderocol for treatment of hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP) caused by susceptible gram-negative microorganisms in patients 18 years of age or older. This was after cefiderocol was initially approved for patients 18 years of age or older for the treatment of complicated urinary tract infections, including pyelonephritis, caused by gram-negative pathogens.

The expanded indication was based on the results of the phase 3 APEKS-NP study, which showed cefiderocol met the primary endpoint of non-inferiority compared to high-dose extended-infusion meropenem in all-cause mortality 14 days after initiation of study drug in the treatment of patients with HABP, VABP and healthcare-associated bacterial pneumonia (HCABP).

Prescribing Practice

Lodise believes this agent can be prescribed for patients who either have carbapenem-resistant infections or at high risk for them. “The nice thing about cefiderocol is that it has activity against enterobacterales, pseudomonas, Acinetobacter baumannii as well as stenotrophomonas,” Lodise said. So really it is a broad spectrum drug that has activity against our major carbapenem-resistant organisms within the United States.”


1. Cai B, Zhou Y, Slover C, et al. Real-world use of cefiderocol treating non-COVID patients with confirmed Gram-negative infections in US hospital during January 2020-June 2022. Poster #2753 presented at IDWeek 2023. October 11-15, 2023. Boston, MA.

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