Clinical Impact of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Associated Clostridioides difficile Infection Among Patients with Lung Cancer

Abstract

Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKIs)-associated Clostridioides difficile infection (CDI) among lung cancer patients have been reported in case reports and adverse events reporting system databases in the United States and Japan, but clinical data remained insufficient. This study aims to evaluate CDI in lung cancer patients receiving EGFR-TKIs. Methods: We conducted a retrospective cohort study using multi-institutional electronic medical records database. We included patients aged older than 20 years diagnosed with lung cancer and treated with EGFR-TKIs (gefitinib, erlotinib, afatinib). We defined EGFR-TKI initiation date as the index date and occurrence of diarrhea with CDI or without CDI as the event date. We followed patients from the index date until the event date, ICU admission, death, or 12/31/2019. Results: We included 2242 diarrhea patients, 51 were EGFR-TKI with CDI cohort, and 2191 were diarrhea without CDI cohort. Patients who were concurrently taking antibiotics (hazard ratio [HR], 3.30; 95% CI, 1.67-6.5) and systemic steroids (HR, 4.9; 95% CI, 2.65-9.06) had an increased risk of CDI. First-generation EGFR-TKIs tended to be associated with an increased risk of CDI compared with afatinib (HR, 1.81, 95% CI, 0.94-3.47). EGFR-TKI with CDI had a higher ICU admission rate (HR, 3.42, 95% CI, and mortality rate (HR, 2.34, 95% CI,) than diarrhea without CDI. Conclusion: Patients with CDI had higher ICU admission rates and mortality rates than those without CDI. Concurrent use of antibiotics and systemic steroids were risk factors for CDI among patients with lung cancer receiving EGFR-TKIs. Afatinib was not associated with a higher risk of CDI than first-generation EGFR-TKIs.

Metabolomic, microbiome and transcriptomic study of crofelemer or loperamide in rat model of afatinib-induced intestine epithelial damage and diarrhea

“…Blautia has been suggested to be abundantly reside in the intestine of neratinib-induced diarrhea rat model (Secombe et al, 2022). A retrospective clinical study by Chung et al showed that the use of first-generation EGFR-TKI increases the risk ofClostridioides difficile infection and diarrhea (Chung et al, 2022). Moreover, both loperamide and crofelemer group showed a significant increase in the abundance of Parasutterella as compared with that of the afatinib group.…”

Molecular docking, dynamics and in vitro analysis of multi-target inhibitors for Clostridioides difficile

“…Therefore, only vancomycin is the preferred FDA approved drug for the treatment [ 15 - 16 ]. As the therapeutic antimicrobial options are limited for CDI due to its rising antibiotic resistance and declining sensitivity, there is an urgent need for the development of novel anti-clostridial drugs [ 17 , 18 , 19 , 20 , 21 ]. Five proteins of C difficile that were reported as drug targets were used [ 22 ].…”

Inhibition of EGFR/ErbB does not protect againstC. difficiletoxin B

“…Emerging clinical evidence suggests TKIs could potentially have a protective role against CDI. In a study assessing the effect of anti-EGFR TKIs on CDI, lung cancer patients with diarrhea due to C. difficile had a longer interval between TKI initiation and diarrhea (median period: 75 days, range: 25 to 376 days) compared with patients who had diarrhea due to other causes (median period: 7 days, range: 0 to 49 days) [24]. The incidence of CDI in this study was 2.2%, which is notably lower compared to another study of cancer patients receiving immune checkpoint inhibitor immunotherapy where the incidence of CDI was 9.7% [25].…”