Seungyeon Lee, Stephanie Fox-Rawlings, PhD, Nina Zeldes, PhD, National Center for Health Research
Urinary tract infections (UTI) typically occur in young, otherwise healthy women. While UTIs can be very unpleasant, most don’t cause serious harm and can be treated with antibiotics, if necessary. However, for people who get a UTI that is resistant to antibiotics, such an infection can become a more serious health issue. UTIs are particularly dangerous in elderly adults or people with other health conditions, and these more dangerous cases are called complicated urinary tract infections (cUTI).
On November 14, 2019, the FDA  approved a new antibiotic called Fetroja (cefiderocol) to treat cUTIs, including kidney infections, for adults with few or no other treatment options. This new antibiotic is given through intravenous (IV) infusions every 8 hours for 7-14 days. Patients with reduced functioning of their kidneys are recommended to get a lower dose.
Fetroja was tested in two clinical trials. The first trial looked at how well the drug worked, and the findings from the second trial were used to learn more about the safety of the drug. However, both of these trials had several shortcomings,which raises questions about whether the FDA should have approved the drug without better studies.
How safe and effective is Fetroja?
The first clinical trial tested Fetroja as a treatment for patients with cUTI, comparing Fetroja to a different antibiotic (imipenem/cilastatin, such as Primaxin). Slightly fewer people taking Fetroja had side effects than people taking the other antibiotic (41% vs 51% respectively). This difference may have occurred due to chance, so we don’t know if Fetroja patients could expect to have fewer side effects than patients taking the other medication. For both drugs, the most common side effects were diarrhea, high blood pressure, constipation, headache and nausea.
The clinical trial also found that symptoms resolved similarly for both treatments. More patients taking Fetroja continued to have reductions in the amount of bacteria and their urine after finishing the treatment, but fewer bacteria does not necessarily mean that patients experienced fewer symptoms. And although the lower levels of bacteria could potentially reduce the chance for a relapse, the study results did not indicate that patients taking Fetroja actually were less likely to relapse in the two weeks after completing treatment.
Another shortcoming of the study is that only 2% of the patients were from the U.S. This could be a problem because health care practices vary in different countries. Patients in the U.S. might have a different experience with Fetroja due to these differences in health care. In addition, about 96% of patients in this clinical trial were white, so it is impossible to know if the drug would be more or less effective for people of color. We told the FDA that they should have demanded the drug be studied on a wider range of racial and ethnic groups.
Additional safety concerns with Fetroja
The second clinical trial was an open label, descriptive study with patients with antibiotic resistant infections, including but not limited to cUTI. An open label study is one where all the patients know they are taking a new drug, which is usually described to them as a promising or exciting new treatment. That can bias the patients into thinking they are feeling better, even if they aren’t. For that reason, it is not a good way to study effectiveness, but it can be a reasonable way to study safety.
The patients included in this second clinical trial had very serious antibiotic resistant infections, such as healthcare-associated pneumonia, bloodstream infection, sepsis, and cUTI. Patients were randomized into one of two groups. The first group of patients were given Fetroja, and the other group received a combination of up to three other antibiotics.
In the group taking Fetroja, more patients died compared to the group taking the other antibiotics. The increase in deaths among the patients taking Fetroja is alarming, and it is not possible to say whether patients given Fetroja were more likely to die because they had more severe conditions. Was the difference just due to chance or was the drug more deadly? While most of the patients who died had pneumonia, blood infections, or sepsis, and did not have cUTI, the study raises questions about whether Fetroja is a safe choice for patients who are experiencing complications from their infections or have other underlying medical conditions.
Fetroja is a new antibiotic to treat complicated urinary tract infections (cUTI). However, we have concerns about the drug because FDA approval was based on two clinical trials that raised questions about safety and effectiveness that were not answered. We don’t know how well the drug works on Americans, and especially people of color. We are also concerned that severely ill patients who took Fetroja were more likely to die than patients taking other types of antibiotics. If you have been prescribed Fetroja and you have any concerns, it is important to speak with your healthcare provider. You can read more about our concerns about FDA’s approval of this drug here.
Fetroja should only be used when the infection is caused by antibiotic resistant bacteria. Otherwise, it would put patients at unnecessary risk and also would increase the chances of bacteria becoming resistant to the new drug in the future.
All articles are reviewed and approved by Dr. Diana Zuckerman and other senior staff.
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 Antimicrobial Drugs Advisory Committee Cefiderocol Briefing Document, NDA ## 209445, October 2019. Available as download here: https://www.fda.gov/media/131705/download. Here is the FDA’s briefing document https://www.fda.gov/media/131703/download