Treatment of critically ill patients with cefiderocol for infections caused by multidrug-resistant pathogens: review of the evidence

Abstract

Appropriate antibiotic treatment for critically ill patients with serious Gram-negative infections in the intensive care unit is crucial to minimize morbidity and mortality. Several new antibiotics have shown in vitro activity against carbapenem-resistant Enterobacterales (CRE) and difficult-to-treat resistant Pseudomonas aeruginosa. Cefiderocol is the first approved siderophore beta-lactam antibiotic with potent activity against multidrug-resistant, carbapenem-resistant, difficult-to-treat or extensively drug-resistant Gram-negative pathogens, which have limited treatment options. The spectrum of activity of cefiderocol includes drug-resistant strains of Acinetobacter baumannii, P. aeruginosa, Stenotrophomonas maltophilia, Achromobacter spp. and Burkholderia spp. and CRE that produce serine- and/or metallo-carbapenemases. Phase 1 studies established that cefiderocol achieves adequate concentration in the epithelial lining fluid in the lung and requires dosing adjustment for renal function, including patients with augmented renal clearance and continuous renal-replacement therapy (CRRT); no clinically significant drug–drug interactions are expected. The non-inferiority of cefiderocol versus high-dose, extended-infusion meropenem in all-cause mortality (ACM) rates at day 14 was demonstrated in the randomized, double-blind APEKS–NP Phase 3 clinical study in patients with nosocomial pneumonia caused by suspected or confirmed Gram-negative bacteria. Furthermore, the efficacy of cefiderocol was investigated in the randomized, open-label, pathogen-focused, descriptive CREDIBLE–CR Phase 3 clinical study in its target patient population with serious carbapenem-resistant Gram-negative infections, including hospitalized patients with nosocomial pneumonia, bloodstream infection/sepsis, or complicated urinary tract infections. However, a numerically greater ACM rate with cefiderocol compared with BAT led to the inclusion of a warning in US and European prescribing information. Cefiderocol susceptibility results obtained with commercial tests should be carefully evaluated due to current issues regarding their accuracy and reliability. Since its approval, real-world evidence in patients with multidrug-resistant and carbapenem-resistant Gram-negative bacterial infections suggests that cefiderocol can be efficacious in certain critically ill patient groups, such as those requiring mechanical ventilation for COVID-19 pneumonia with subsequently acquired Gram-negative bacterial superinfection, and patients with CRRT and/or extracorporeal membrane oxygenation. In this article, we review the microbiological spectrum, pharmacokinetics/pharmacodynamics, efficacy and safety profiles and real-world evidence for cefiderocol, and look at future considerations for its role in the treatment of critically ill patients with challenging Gram-negative bacterial infections.

Cefiderocol: early clinical experience for multi-drug resistant gram-negative infections

“…With very few options for MBL-producing pathogens, CFDC remains an important antimicrobial and has been recommended along with a combination of aztreonam and avibactam ( 5 , 31 , 32 ). Another important finding from our study was that there was no difference in clinical outcomes between patients who received CFDC combination therapy or monotherapy, which generally supports other findings that have found no difference ( 33 ).…”

Prolonged versus intermittent β-lactam infusion in sepsis: a systematic review and meta-analysis of randomized controlled trials

“…In critically ill patients, particularly during the early phases of severe sepsis and septic shock, pathophysiological changes alter the pharmacokinetics of β-lactam antibiotics [ 45 ]. These patients experience an increased volume of distribution and accelerated drug clearance, resulting in lower initial drug concentrations [ 8 , 45 ]. Consequently, administering a loading dose before the continuous infusion of β-lactam antibiotics can help maintain drug concentrations above the MIC and reduce the risk of treatment failure [ 11 ].…”

“…β-Lactam antibiotics are the most widely used broad-spectrum antibiotics globally, especially for critically ill patients [ 6 – 8 ]. They exhibit time-dependent pharmacodynamics, wherein maintaining a drug concentration above the minimum inhibitory concentration (MIC) for an adequate duration is crucial for efficacy [ 7 , 9 ].…”

How to treat severe Acinetobacter baumannii infections

“…Cefiderocol is clinically active in infections caused by MDR and XDR infections caused by AB [118 ▪▪ ,119 ▪ ]. This has been demonstrated in three randomised, prospective, clinical trials in patients at risk of infection with MDR or carbapenem-resistant Gram-negative bacteria [120–122].…”