Cefiderocol a promising treatment for multidrug-resistant complicated UTI
Intravenous cefiderocol thrice daily is noninferior to imipenem-cilastatin for treating complicated urinary tract infection (UTI) patients with multidrug-resistant, Gram-negative infections, according to a recent study.
“Cefiderocol has broad in-vitro activity against Gram-negative pathogens, including multidrug-resistant and carbapenem-resistant strains, and a safety profile that seems to be similar to that of other cephalosporins, indicating that it is a promising drug for use in patients with limited treatment options due to antimicrobial resistance or drug-related toxicities,” said researchers.
The trial included 371 complicated UTI patients who received either intravenous cefiderocol 2 g (n=252; mean age 62.3±16.10 years; 53 percent female) or imipenem-cilastatin 1 g each (n=119; mean age 61.3±18.48 years; 60 percent female). The most common baseline uropathogens were Escherichia coli and Klebsiella pneumoniae. [Lancet Infect Dis 2018;doi:10.1016/S1473-3099(18)30554-1]
After a median treatment duration of 9.0 days in both treatment arms, the primary composite outcome of clinical and microbiological response was achieved by 73 percent (n=183) and 55 percent (n=119) in the cefiderocol and imipenem-cilastatin groups, respectively. The resulting adjusted treatment difference of 18.58 percent (95 percent CI, 8.23–28.92; p=0.0004) was statistically significant.
Taken separately, the proportion of participants who achieved microbiological response was significantly higher in the cefiderocol group (treatment difference, 17.25 percent; 6.92–27.58). No between-group difference was reported for clinical response (treatment difference, 2.39 percent; –4.66 to 9.44).
“This met the criterion for noninferiority at the prespecified 20 percent and 15 percent margins,” said researchers.
Subsequent sensitivity analyses according to participant age, sex and clinical diagnosis did not meaningfully change the initial results: Cefiderocol remained noninferior to imipenem-cilastatin.
In posthoc analysis, researchers noted that “cefiderocol was superior to imipenem-cilastatin. The absolute difference of 18·58 percent in the composite primary endpoint was consistent across all analysed populations and clinical diagnostic groups with complicated urinary tract infection, and was driven by the difference in microbiological eradication.”
Through in-hospital daily monitoring, researchers also compared the safety and tolerability of both treatments. They found that 41 percent and 51 percent of the cefiderocol and imipenem-cilastatin groups had adverse events, respectively. Majority of the cases were mild or moderate in severity.
Only 5 percent and 8 percent of the corresponding treatment arms developed serious adverse events, the most common of which was Clostridium difficile colitis. One death was reported in the cifederocol group due to cardiac arrest, though it was ruled as unrelated to the trial by the investigators.
“Although designed as a noninferiority study, the results strongly favoured cefiderocol,” researchers said, noting that the comparatively better rate of microbiological eradication was not due to resistance to imipenem.
“[W]hen the results of this study are combined with findings from numerous animal infection studies involving deep tissue, lung and bacteraemia whereby the pharmacokinetic profiles in animals mimic the human pharmacokinetic profile, cefiderocol could be an important new antibiotic to treat highly resistant Gram-negative bacteria,” they added.