cefiderocol and Cystic-Fibrosis

To evaluate the activity of cefiderocol against sequential P. aeruginosa isolates from chronically-infected cystic fibrosis patients as well as to investigate the potential mechanisms involved in resistance through whole genome sequencing.. Three sequential P. aeruginosa isolates from each of 50 chronically-colonized cystic fibrosis patients were studied. MICs for novel and classical antipseudomonal agents were determined by broth microdilution and whole genome sequences (n = 150) were obtained to investigate the presence of mutations within a set of chromosomal genes involved in P. aeruginosa antibiotic resistance (n = 40) and iron uptake (n = 120).. Cefiderocol showed the lowest MIC. Cefiderocol resistance is modulated by a complex mutational resistome, potentially conferring cross-resistance to novel beta-lactam beta-lactamase combinations, as well as an extended list of mutated iron-uptake genes. Monitoring the acquisition of mutations in all these genes will be helpful to guide treatments and mitigate the emergence and spread of resistance to this novel antibiotic.

Topics: Anti-Bacterial Agents; beta-Lactamases; Cefiderocol; Cephalosporins; Cystic Fibrosis; Drug Resistance, Multiple, Bacterial; Genomics; Humans; Iron; Microbial Sensitivity Tests; Pseudomonas aeruginosa

The emergence and spread of antimicrobial resistance (AMR) in Gram-negative pathogens, such as carbapenem-resistant Pseudomonas aeruginosa, pose an increasing threat to health care. Patients with immunodeficiencies or chronic pulmonary disease, like cystic fibrosis (CF), are particularly vulnerable to Pseudomonas infections and depend heavily on antibiotic therapy. To broaden limited treatment options, this study evaluated the potency of the recently licensed drugs ceftazidime-avibactam (CZA), ceftolozane-tazobactam (C/T), and cefiderocol (FDC) as well as two novel preclinical antibiotics, darobactins B (DAR B) and B9 (DAR B9), against clinical P. aeruginosa isolates derived from respiratory samples of CF patients. We observed high levels of resistance to all three newly licensed drugs, with cefiderocol exhibiting the best activity. From the 66 investigated P. aeruginosa isolates, a total of 53% were resistant to CZA, 49% to C/T, and 30% to FDC. Strikingly, 52 of the evaluated isolates were obtained from CF patients prior to market introduction of the drugs. Thus, our results suggest that resistance to CZA, C/T, and FDC may be due to preexisting resistance mechanisms. On the other hand, our two novel preclinical compounds performed better than (CZA and C/T) or close to (FDC) the licensed drugs-most likely due to the novel mode of action. Thus, our results highlight the necessity of global consistency in the area of antibiotic stewardship to prevent AMR from further impairing the potency of antibiotics in clinical practice. Ultimately, this study demonstrates the urgency to support the development of novel antimicrobials, preferably with a new mode of action such as darobactins B and B9, two very promising antimicrobial compounds for the treatment of critically ill patients suffering from multidrug-resistant Gram-negative (MRGN) infections.

Topics: Adolescent; Anti-Bacterial Agents; Cefiderocol; Cephalosporins; Child; Cystic Fibrosis; Drug Resistance, Multiple, Bacterial; Humans; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Pseudomonas Infections; Tazobactam

Treatment options for Achromobacter xylosoxidans are limited. Eight cystic fibrosis patients with A. xylosoxidans were treated with 12 cefiderocol courses. Pretreatment in vitro resistance was seen in 3 of 8 cases. Clinical response occurred after 11 of 12 treatment courses. However, microbiologic relapse was observed after 11 of 12 treatment courses, notably without emergence of resistance.

Topics: Achromobacter denitrificans; Adult; Anti-Bacterial Agents; Cefiderocol; Cephalosporins; Child; Cystic Fibrosis; Gram-Negative Bacterial Infections; Humans

We are writing this letter to provide an update of published information on antibiotics for cystic fibrosis (CF) pulmonary exacerbations to the State of the Art articles by Zobell et al. Information on meropenem-vaborbactam and cefiderocol were not available when the original articles were published. These new antibiotics, approved in 2017 and 2019, possess antipseudomonal properties like the other carbapenems and cephalosporins in the original articles however, existing literature refers to their use for other less common bacteria. As patients with CF age, the microorganisms in their bacterial cultures change and some can colonize multiple or uncommon bacterial species including, Burkholderia, Achromobacter, and Stenotrophomonas spp. In 2019, these nonlactose fermenting bacterial species made up for approximately 15% of respiratory microorganisms cultured in pediatric patients. Though infrequent, compared to Staphylococcus aureus or Pseudomonas aeruginosa, these bacteria are opportunistic pathogens and patients at the highest risk for these infections include those with CF. Like other Gram negative bacteria, Burkholderia, Achromobacter, and Stenotrophomonas spp., are frequently drug resistant and can make treatment extremely challenging, thus it is crucial that data for treatment of these less common pathogens be evaluated.

Topics: Anti-Bacterial Agents; Boronic Acids; Cefiderocol; Cephalosporins; Child; Cystic Fibrosis; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Meropenem

Cystic fibrosis is associated with significant morbidity and early mortality due to recurrent acute and chronic lung infections. The chronic use of multiple antibiotics without pathogen eradication increases the possibility of extensive drug resistance or even pan-drug resistance (PDR). It is imperative that new or alternative treatment options be explored. We present a clinical case of a 10-year-old female cystic fibrosis patient, infected with a PDR Achromobacter spp. She was treated with cefiderocol, meropenem/vaborbactam, and bacteriophage therapy (Ax2CJ45ϕ2) during two separate admissions in an attempt to clear her infection and restore baseline pulmonary function. The Centers for Disease Control and Prevention confirmed antibiotic susceptibilities, which showed resistance to both cefiderocol and meropenem/vaborbactam. However, after using all three agents concomitantly during the second treatment course, our patient's pulmonary function improved dramatically, and the Achromobacter spp. could not be isolated from sputum samples obtained 8 and 16 weeks after completion of therapy. Overall, the treatment regimen consisting of cefiderocol, meropenem/vaborbactam, and bacteriophage was safe and well-tolerated in our patient.

Topics: Achromobacter; Anti-Bacterial Agents; Bacteriophages; Boronic Acids; Cefiderocol; Cephalosporins; Child; Combined Modality Therapy; Cystic Fibrosis; Drug Combinations; Drug Resistance, Bacterial; Drug Resistance, Multiple; Female; Gram-Negative Bacterial Infections; Heterocyclic Compounds, 1-Ring; Humans; Meropenem