Abstract
Treatment of multidrug-resistant (MDR) Gram-negative bacteria (GNB) infections has led to a global public health challenging due to the bacterial resistance and limited choices of antibiotics. Cefiderocol (CFDC), a novel siderophore cephalosporin possessed unique drug delivery systems and stability to β-lactamases, has the potential to become first-line therapy for most aggressive MDR Gram-negative pathogens infection. However, there have been reports of drug resistance in the course of using CFDC. This study provides an overview of the in-vitro and in-vivo activity of CFDC and potential resistance mechanism was also summarized. In general, CFDC shows excellent activity against a broad range of MDR GNB pathogens including Enterobacteriaceae, Klebsiella pneumoniae, Pseudomonas aeruginosa, Acinetobacter baumannii, and Stenotrophomonas maltophilia. The expressions of metallo-β-lactamases such as inosine 5'-monophosphate (IMP), Verona integron-mediated metallo-β-lactamase (VIM), and New Delhi metallo-β-lactamase (NDM) are associated with a higher resistance rate of CFDC. Carbapenem-resistant phenotype has little effect on the resistance rate, although the acquisition of a particular carbapenemase may affect the susceptibility of the pathogens to CFDC. For potential resistance mechanism, mutations in β-lactamases and TonB-dependent receptors, which assist CFDC entering bacteria, would increase a minimum inhibitory concentration (MIC)90 value of CFDC against MDR pathogens. Since the development of CFDC, resistance during its utilization has been reported thus, prudent clinical applications are still necessary to preserve the activity of CFDC.
Highlights
As an ongoing challenge to global health, the emergence of antibiotic-resistant infections results in substantial morbidity and mortality (1)
We aim to review the in-vitro and invivo activity of CFDC to evaluate its global effectiveness so far (Supplementary Table 1) and to discuss the potential mechanism of CFDC resistance
C Paul et al have reported that the resistance rate of 15 carbapenem-resistant K. pneumoniae is up to 20% based on the Clinical and Laboratory Standards Institute (CLSI) breakpoints, with an MIC90 value of 32 mg/l (20)
Summary
As an ongoing challenge to global health, the emergence of antibiotic-resistant infections results in substantial morbidity and mortality (1). As a novel injectable siderophore cephalosporin, cefiderocol (CFDC) has been approved by the United States Food and Drug Administration (FDA) for the treatment of complicated urinary tract infections (cUTIs) in 2019, hospital-acquired bacterial pneumonia (HABP), and ventilator-associated bacterial pneumonia (VABP) caused by GNB in 2020. Through binding to bacterial iron transporter outer membrane protein, CFDC can enter the bacterial periplasmic space to avoid the degradation of β-lactamase produced by the pathogen (7, 8) (Figure 1). It shows activity against GNB pathogens including extended-spectrum β-lactamases (ESBL)-producing GNB, CRE, P. aeruginosa, A. baumannii, K. pneumoniae, Klebsiella oxytoca, and Stenotrophomonas maltophilia (S. maltophilia) (9–19). Broth microdilution and disk diffusion methods are both available for different standards
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