Outline: Chronic infection with the Burkholderia cepacia complex (BCC) in cystic fibrosis patients is associated with increased morbidity and mortality and thus represents a significant challenge in the treatment of patients suffering from CF. The BCC currently comprises at least 22 closely related species that are typically of a multi-resistant phenotype. Moreover, no antibiotic regime exists neither for eradication nor for the antibiotic treatment of chronic BCC lung infection. Question: The aim of this study was to assess the susceptibility of BCC to the new cephalosporines ceftolozane/tazobactam (CTB), ceftazidime/avibactam (CZA) and cefiderocol (FDC). Further, using whole genome sequencing (WGS) we want to get more insights into the molecular epidemiology and the relatedness of German BCC isolates. Methods: Antimicrobial activities of CZA, CTB and FDC were tested against BCC isolates (n = 100) recovered from individual CF patients by using the gold standard broth microdilution (BMD). BCC species of this study were B. cenocepacia (n=39), B. multivorans (n=35), B. ambifaria (n=1), B. cepacia (n=4), B. contaminans (n=4), B. diffusa (n=1), B. stabilis (n=8), B. vietnamiensis (n=6), and B. arboris (n=2). BCC isolates (the first/earliest available isolate of each individual patient was selected) derive from CF patients treated at University hospital Frankfurt/Munich (including isolates submitted to the respective Consiliary Laboratory of CF Bacteriology). For WGS, DNA of cultured bacteria was extracted using DNeasy UltraClean 96 Kit. Library preparation and sequencing was performed by a commercial service provider (Novogene, Cambridge,UK) using Illumina chemistry. Results: Finally, CTB, CZA and FDC susceptibility rates were 75%, 92%, 91% (by using EUCAST breakpoints available for P. aeruginosa). Sequence analysis based on a cgMLST sheme is currently under way, but determination of the standard seven gene MLST sheme showed that 32% of isolates belong to so far unknown MLST types that will currently be newly assigned. Conclusion: CTB, CZA and FDC are highly active against BCC species from CF patients and may be effective alternative therapeutic options.