New antibiotic should be called "Trojan horse" …

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Florham Park, NJ – A new "siderophore" cephalosporin that enters the bacterium with an iron transporter and simultaneously bypbades several resistance mechanisms has been reported in a Phase 2 study in Infectious diseases lancet (2018, doi: 10.1016 / S1473-3099 (18) 30554-1) during urobad infections have pbaded the non-inferiority test compared to standard treatment with imipenem cilastatin.

Gram-negative bacteria have developed 3 different mechanisms of resistance to escape the attack of cephalosporins. Mutations in the porin gene prevent antibiotics from entering the bacteria through the pores. In the bacterial cell itself, the antibiotics are degraded by enzymes (beta-lactamases) or eliminated by means of efflux pumps.

The Japanese pharmaceutical company Shionogi Seiyaku has modified the structure of the cephalosporin so that it can escape the mechanisms of resistance, such as a Trojan horse. To this end, the molecule has been extended by a catechol, which binds free iron as a chelate. For entry into the bacterium, S-649266 or Cefiderocol then uses the active iron transporter, essential for bacteria because their metabolism relies on iron. Cefiderocol is also resistant to all beta-lactamases and, according to the manufacturer, it can not be eliminated via efflux pumps.

After in vitro studies showed good activity against a number of Gram-negative bacteria, including A. baumannii resistant, P. aeruginosa and S. maltophilia, and that preclinical studies did not present a risk of developing. safety, cefiderocol became a phase -2 study tested.

The study involved 448 adults with complicated urinary tract infection or simple pyelonephritis. Patients received 3 daily infusions of cefiderocol (300 patients) or imipenem cilastatin (148 patients) in 67 hospitals in 13 countries for 7 to 14 days.

A Gram-negative bacterium was detected in 252 patients of the cefiderocol group and 119 patients of the imipenem-cilastatin group. E. coli, K. pneumoniae or P. aeruginosa constituted the majority of participants: approximately half of K. pneumoniae isolates were resistant to cefepime and levofloxacin, one-third of E. coli isolates were resistant to cefepime and levofloxacin. Coli were insensitive to levofloxacin and more than one-tenth of E isolates. coli did not respond to cefepime during resistance tests.

As reported by Simon Portsmouth of Shionogi in Florham Park, New Jersey and colleagues in the cefiderocol group, 73% of patients achieved the primary endpoint, a combination of clinical improvement and microbiological response, against 55% in the imipenem-cilastatin group. Cefiderocol therefore had a better effect than the current standard treatment. The difference of 18.58 percentage points was significant with a 95% confidence interval of 8.23 ​​to 28.92 percentage points and met the given non-inferiority criterion.

Cefiderocol was well tolerated by most patients. Adverse events occurred in 122 of the 300 patients (41%) in the cefiderocol group compared to 76 of the 148 patients (51%) in the imipenem-cilastatin group. The most common gastrointestinal disorders were diarrhea, constipation, nausea, vomiting and abdominal pain. They occurred in 35 patients (12%) of the cefiderocol group and 27 patients (18%) of the imipenem cilastatin group. 14 patients (5%) of the cefiderocol group and 12 patients (8%) of the imipenem-cilastatin group had at least one serious adverse event. Most often, it was a C. difficile infection.

The manufacturer has now initiated two phase 3 studies (CREDIBLE-CR and APEKS-NP), which, if completed, should lead to the approval of the new compound, particularly since the FDA (Food and Drug Administration) recently raised the bar for new antibiotics has dropped. It is impossible to predict whether antibiotics clinically improve the treatment of resistant infections or whether new resistance mechanisms are developing rapidly. However, all experts agree that it is urgent to find new antibiotics. © heat / aerzteblatt.de