Occurrence of High Levels of Cefiderocol Resistance in Carbapenem-Resistant Escherichia coli before Its Approval in China: a Report from China CRE-Network.

Cefiderocol has been approved in the United States and Europe but not in China. We aim to evaluate carbapenem-resistant Enterobacterales (CRE) susceptibility to cefiderocol to provide baseline data and investigate the resistance mechanism. From 2018 to 2019, 1,158 CRE isolates were collected from 23 provinces and municipalities across China. The MICs of antimicrobials were determined via the agar dilution and broth microdilution methods. Whole-genome sequencing was performed for 26 cefiderocol-resistant Escherichia coli isolates to investigate the resistance mechanism. Clone transformations were used to explore the function of cirA, pbp3, and blaNDM-5 in resistance. Among the 21 antimicrobials tested, aztreonam-avibactam had the highest antibacterial activity (98.3%), followed by cefiderocol (97.3%) and colistin (95.3%). A total of 26 E. coli isolates harboring New Delhi metallo-beta-lactamase 5 (NDM-5) showed high levels of cefiderocol resistance, of which sequence type 167 (ST167) accounted for 76.9% (20/26). We found 4 amino-acid insertions (YRIN/YRIK) at position 333 of penicillin-binding protein 3 (PBP3) in the 26 E. coli isolates, and 22 isolates had a siderophore receptor cirA premature stop codon. After obtaining the wild-type cirA supplementation, the MIC of the transformants decreased by 8 to 16 times in two cefiderocol-resistant isolates. A cefiderocol-susceptible isolate harboring NDM-5 has an MIC increased from 1 µg/mL to 64 µg/mL after cirA deletion, and the MIC decreased from 64 µg/mL to 0.5 µg/mL after blaNDM-5 deletion. The MIC of the E. coli DH5α, from which the pbp3 mutant was obtained, increased from 0.064 µg/mL to 0.25 µg/mL. Cefiderocol showed activity against most CRE in China. The resistance of ST167 E. coli to cefiderocol is a combination of the premature stop codon of cirA, pbp3 mutation, and blaNDM-5 existence. IMPORTANCE Cefiderocol, a new siderophore cephalosporin, has been approved in the United States and Europe but not in China. At present, there are almost no antimicrobial susceptibility evaluation data on cefiderocol in China. We evaluated the in vitro susceptibility of 1,158 strains of carbapenem-resistant Enterobacterales to cefiderocol and other antibiotics. We found that a high proportion of Escherichia coli showed high-level resistance to cefiderocol. Whole-genome sequencing (WGS) and molecular cloning experiments confirmed that the synergistic effect of the cirA gene premature stop codon, blaNDM-5 existence, and the pbp3 mutation is associated with high levels of cefiderocol resistance.

A case of AIDS complicated with Pneumocystis jirovecii pneumonia and disseminated infection of Talaromyces marneffei and Cryptococcus neoformans / 中国热带医学

@#Abstract: AIDS combined with Pneumocystis jirovecii pneumonia (PJP) and disseminated infections of Talaromyces marneffei and Cryptococcus neoformans are rare. This paper summarizes and analyzes the diagnosis and treatment of an AIDS patient with multiple fungal infections for reference. A 79-year-old male patient was admitted to the hospital with "stool habit change for more than 20 days". The white blood cell count was 4.57×109/L, the percentage of neutrophils was 81.8%, the absolute count of CD4+ lymphocytes was 6/μL, and the CD4/CD8 ratio was 0.17. HIV antibody positive was confirmed by CDC. The cerebrospinal fluid and alveolar lavage fluid were positive for Cryptococcus neoformans capsular antigen, and Pneumocystis jirovecii was found by the bronchoalveolar lavage fluid stained with hexamine silver. The cerebrospinal fluid culture was positive for Cryptococcus neoformans, and the blood culture was positive for Cryptococcus neoformans and Talaromyces marneffei. CT showed that bronchovascular bundles in both lungs were more thick, patchy and cable-like high-density shadows were seen in both lungs, and the edges were blurred. Nodular and cable-like high-density shadows were seen in the posterior apical segment of the left upper lobe, with clear margins. Infection of both lungs was considered, and secondary pulmonary tuberculosis occurred in the left upper lobe. After admission, the patient was treated with various anti-bacterial and fungal drugs due to recurrent fever, but the effect was not effective. The fever symptoms of the patient could not be significantly improved, and his condition continued to worsen, and he eventually died. The patient with AIDS complicated with bacterial and fungal infection, especially PJP infection in serious condifiton and has a poor prognosis for rapid development, so clinical attention should be paid to.