Cefiderocol was non-inferior to high-dose, extended infusion meropenem in patients with Gram-negative nosocomial pneumonia, according to a study published in The Lancet Infectious Diseases.
In this randomized, phase 3, non-inferiority trial, adults aged 18 years or older with hospital-acquired, ventilator- or, healthcare-associated Gram-negative pneumonia were enrolled. Participants were randomized to receive 3-hour intravenous infusions of either cefiderocol 2 g or meropenem 2 g every 8 hours for 7 to 14 days. All patients were also given open-label 600 mg intravenous linezolid every 12 hours for at least 5 days. The primary endpoint was all-cause mortality at day 14 in the modified intention-to-treat population (mITT). Key secondary endpoints were clinical and microbiological outcomes per treatment group at test of cure defined as 7 days ± 3 days after end of treatment.
Of the 300 patients enrolled, 148 were assigned to receive cefiderocol and 152 were assigned to receive meropenem. The mITT population included 292 patients, as 3 patients from each group were excluded with Gram-positive only pneumonia and a further 2 excluded from the meropenem group. The microbiologically evaluable per-protocol (ME-PP) involved 206 patients, with 105 in the cifederocol group and 101 patients in the meropenem group, and included patients in the mITT population without major protocol violations.
Within the mITT population, 251 patients (86%) had a qualifying baseline Gram-negative pathogen, which included Klebsiella pneumoniae (n=92), Pseudomonas aeruginosa (n=48), Acinetobacter baumannii (n=47), and Escherichia coli (n=41). At baseline, an acute physiology chronic health evaluation (APACHE) II score of 16 or higher was observed in 142 patients (49%); 175 patients (60%) required mechanical ventilation and 199 patients (68%) were in intensive care units when randomized.
The cefiderocol MIC90 values for the most frequent pathogens in the mITT population ranged between 0.5 μg/mL and 2.0 μg/mL. Data showed that 30 of 124 patients who received cefiderocol and 26 of 127 patients who received meropenem had a pathogen with a meropenem MIC of more than 8 μg/mL. All-cause mortality at day 14 was 12.4% (18/145) for the cefiderocol group and 11.6% (17/146) for the meropenem group (95% CI, -6.6 to 8.2; P =.002 for non-inferiority).
All-cause mortality at day 28 rates were similar between treatment groups in patients with APACHE II scores of at least 20, with previous empirical treatment failure, and who were in the ICU when randomization occurred.
In the cefiderocol group, 94 of 145 patients achieved clinical cure compared to 98 of 147 patients in the meropenem group (adjusted treatment difference, -2.0; 95% CI, -12.5 to 8.5). Proportion of microbial eradication at test of cure was seen in 59 of 124 patients in the cefiderocol group and 61 of 127 patients in the meropenem group (adjusted treatment different, -1.4; 95% CI, -13.5 to 10.7). The clinical and microbiological outcomes at test of cure were similar in both groups for most common baseline pathogens.
Treatment-emergent adverse events (TEAE) occurred in 130 of 148 patients (88%) in the cefiderocol group and in 129 of 150 patients (86%) in the meropenem group. Urinary tract infection was the most common TEAE in the cefiderocol group (23/148) and hypokalemia was the most common TEAE in the meropenem group (23/150). Two participants in each group discontinued the study due to drug-related adverse events. By the end of the study, 27% of patients in the cefiderocol group (28/142) had died vs 23% of patients in the meropenem group (34/146).
Investigators said the study was limited because the use of bronchoalveolar lavage for the diagnosis of pneumonia was not mandated. Also, the subgroup analyses were not powered for conclusive treatment comparisons.
Results suggest that day 14 all-cause mortality in patients receiving cefiderocol monotherapy was non-inferior to high-dose, extended-infusion meropenem monotherapy. Furthermore, cefiderocol was well-tolerated and has a safety profile consistent with other cephalosporins or carbapenems, said investigators. “These results also suggest that cefiderocol might be an appropriate option for the treatment of nosocomial pneumonia in patients at risk of multi-drug resistant infections,” investigators concluded.
Disclosure: Several study authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.
Wunderink RG, Matsunaga Y, Ariyasu M, et al. Cefiderocol versus high-dose, extended-infusion meropenem for the treatment of Gram-negative nosocomial pneumonia (APEKS-NP): a randomised, double-blind, phase 3, non-inferiority trial. Lancet Infect Dis. Published online October 12, 2020. doi: 10.1016/S1473-3099(20)30731-3.