Side Effects of Cefiderocol
Cefiderocol is generally well tolerated with predominantly mild gastrointestinal side effects, though serious adverse events including higher mortality rates have been observed in certain patient populations, particularly those with hospital-acquired/ventilator-associated bacterial pneumonia. 1
Common Side Effects
The most frequently reported adverse events with cefiderocol are gastrointestinal in nature and typically mild 1, 2, 3:
- Diarrhea - most common GI complaint 1, 4
- Constipation 1, 4
- Nausea 1, 4
- Vomiting 1, 4
- Abdominal pain (including upper abdominal pain) 1, 4
In the phase 2 cUTI trial, adverse events occurred in 41% of cefiderocol-treated patients versus 51% of imipenem-cilastatin patients, with gastrointestinal disorders being most common (12% vs 18% respectively) 4. The side effect profile is comparable to other cephalosporin antimicrobials 2.
Infusion-Related Adverse Events
Hematologic Effects
- Neutropenia has been reported 1
Renal and Urinary Effects
- Chromaturia (discoloration of urine) 1
- Risk of adverse reactions may be greater in patients with impaired renal function, as cefiderocol is substantially excreted by the kidney 1
Laboratory Test Interference
Cefiderocol may cause false-positive results in urine dipstick tests for protein, ketones, or occult blood, requiring alternate clinical laboratory methods to confirm positive tests 1.
Serious Adverse Events and Mortality Concerns
Critical Safety Signal in Pneumonia Patients
Two phase III clinical trials (CREDIBLE-CR and APEKS-NP) demonstrated higher all-cause mortality associated with cefiderocol treatment in patients with pneumonia 3. This represents the most significant safety concern with this agent.
In the HABP/VABP trial, observed all-cause mortality rates at Day 14 varied by age group 1:
- Patients <65 years: 12.3% (cefiderocol) vs 10.3% (meropenem)
- Patients 65-74 years: 7.5% (cefiderocol) vs 17.8% (meropenem)
- Patients ≥75 years: 17.5% (cefiderocol) vs 9.1% (meropenem)
Rare Serious Events
- One death occurred due to witnessed aspiration during colonoscopy administration (in FMT context, not directly cefiderocol-related) 5
- Urticaria leading to discontinuation has been reported 6
Allergy and Cross-Reactivity Considerations
Patients with suspected non-severe, delayed-type allergy to ceftazidime or cefiderocol should avoid aztreonam when the index reaction occurred <1 year ago 5. This reflects the structural similarity between cefiderocol and ceftazidime, as cefiderocol has a similar chemical structure with a catechol group modification 2.
Special Population Considerations
Elderly Patients
No overall differences in safety were observed between elderly patients (≥65 years) and younger patients in the cUTI trial 1. However, elderly patients are more likely to have decreased renal function, requiring careful dose selection and renal function monitoring 1.
Renal Impairment
The risk of adverse reactions may be greater in patients with impaired renal function 1. Single 1000-mg intravenous doses were generally well tolerated in subjects with impaired renal function except for one subject who discontinued due to urticaria 6.
Pregnancy and Lactation
No available data exist on cefiderocol use in pregnant women 1. Cefiderocol-derived radioactivity was detected in milk of lactating rats, suggesting likely presence in human milk 1.
Clinical Context and Recommendations
The use of cefiderocol should be limited to treatment of complicated urinary tract infections from Gram-negative bacteria, especially in patients who have limited or no alternative treatment options, given the mortality signal observed in pneumonia trials 3. The overall tolerability profile is favorable for cUTI indications, with adverse events being predominantly mild and self-limiting 2, 4.