Drug Interactions between bismuth subsalicylate / metronidazole / tetracycline and durvalumab

ADJUST DOSING INTERVAL: Administration of a bismuth-containing preparation within two to three hours of a tetracycline may significantly decrease serum tetracycline concentrations. Data are available for tetracycline and doxycycline. The proposed mechanism is chelation of tetracycline by bismuth.

MANAGEMENT: Administration of a tetracycline and bismuth-containing preparation should be separated by two to three hours. Patients should be monitored for diminished tetracycline efficacy.

MONITOR: Use of systemic antibiotics during or close to therapy with immune checkpoint inhibitors (ICIs) such as anti-cytotoxic T-lymphocyte-associated protein (CTLA)-4 monoclonal antibodies and/or inhibitors of programmed cell death-1 (PD-1)/programmed death ligand-1 (PD-L1) may result in reduced clinical efficacy of the ICI. The exact mechanism of this interaction has not been fully characterized, but may be related to alterations in the gut microbiota by the systemic antibiotic, potentially resulting in immune dysregulation and a decreased response to the ICI. A meta-analysis of 6 studies involving nivolumab for the treatment of advanced or metastatic non-small cell lung cancer (NSCLC) found that the median progression-free survival (PFS) and overall survival (OS) were reduced by 1.6 months and 8.8 months, respectively, in patients who were exposed to systemic antibiotics before, during, or after nivolumab therapy. Similarly, a single-site retrospective review of patients (n=291) with advanced cancer (melanoma, NSCLC, or renal cell carcinoma) treated with ICI(s) also revealed poorer clinical outcomes associated with the receipt of systemic antibiotics. This study divided patients into 3 groups: no antibiotics, single course of antibiotics, or cumulative courses of antibiotics (i.e., administration of concurrent or successive antibiotics for >7 days) during the 2 weeks prior to and 6 weeks after ICI treatment. The median PFS (6.3 months vs. 3.7 months vs. 2.8 months, respectively) and median OS (21.7 months vs. 17.7 months vs. 6.3 months, respectively) decreased as the antibiotic use increased, though the difference between no antibiotic use and cumulative courses of antibiotics was the only difference determined to be clinically significant. Additionally, a different retrospective analysis of patients (n=635) with advanced cancer treated with ICIs found that antibiotic use was associated with significantly shorter median OS (8 months vs. 23 months), median PFS (4 months vs. 7 months), as well as a reduction in tumor response (57% vs. 71%) when compared to patients who did not receive antibiotics. In contrast, a retrospective study of patients (n=302) with stage IV NSCLC treated with first-line chemo-immunotherapy combinations (i.e., ICI and cytotoxic chemotherapy) had similar OS, PFS, and objective response rate between those who did and did not receive antibiotics during the 30 days prior to initiating an ICI. The receipt of concurrent systemic antibiotics in this patient population was likewise not associated with changes in OS nor PFS.

MANAGEMENT: Until more information is available, caution and clinical monitoring for reduced efficacy of immune checkpoint inhibitors (ICIs) are advised if systemic antibiotics are indicated prior to, concurrently with, or after an ICI. Antibiotic use should be limited to clinically appropriate indications and durations. Clinicians should consult relevant literature, local and national treatment guidelines, and package labeling for further guidance.

MONITOR: Use of systemic antibiotics during or close to therapy with immune checkpoint inhibitors (ICIs) such as anti-cytotoxic T-lymphocyte-associated protein (CTLA)-4 monoclonal antibodies and/or inhibitors of programmed cell death-1 (PD-1)/programmed death ligand-1 (PD-L1) may result in reduced clinical efficacy of the ICI. The exact mechanism of this interaction has not been fully characterized, but may be related to alterations in the gut microbiota by the systemic antibiotic, potentially resulting in immune dysregulation and a decreased response to the ICI. A meta-analysis of 6 studies involving nivolumab for the treatment of advanced or metastatic non-small cell lung cancer (NSCLC) found that the median progression-free survival (PFS) and overall survival (OS) were reduced by 1.6 months and 8.8 months, respectively, in patients who were exposed to systemic antibiotics before, during, or after nivolumab therapy. Similarly, a single-site retrospective review of patients (n=291) with advanced cancer (melanoma, NSCLC, or renal cell carcinoma) treated with ICI(s) also revealed poorer clinical outcomes associated with the receipt of systemic antibiotics. This study divided patients into 3 groups: no antibiotics, single course of antibiotics, or cumulative courses of antibiotics (i.e., administration of concurrent or successive antibiotics for >7 days) during the 2 weeks prior to and 6 weeks after ICI treatment. The median PFS (6.3 months vs. 3.7 months vs. 2.8 months, respectively) and median OS (21.7 months vs. 17.7 months vs. 6.3 months, respectively) decreased as the antibiotic use increased, though the difference between no antibiotic use and cumulative courses of antibiotics was the only difference determined to be clinically significant. Additionally, a different retrospective analysis of patients (n=635) with advanced cancer treated with ICIs found that antibiotic use was associated with significantly shorter median OS (8 months vs. 23 months), median PFS (4 months vs. 7 months), as well as a reduction in tumor response (57% vs. 71%) when compared to patients who did not receive antibiotics. In contrast, a retrospective study of patients (n=302) with stage IV NSCLC treated with first-line chemo-immunotherapy combinations (i.e., ICI and cytotoxic chemotherapy) had similar OS, PFS, and objective response rate between those who did and did not receive antibiotics during the 30 days prior to initiating an ICI. The receipt of concurrent systemic antibiotics in this patient population was likewise not associated with changes in OS nor PFS.

MANAGEMENT: Until more information is available, caution and clinical monitoring for reduced efficacy of immune checkpoint inhibitors (ICIs) are advised if systemic antibiotics are indicated prior to, concurrently with, or after an ICI. Antibiotic use should be limited to clinically appropriate indications and durations. Clinicians should consult relevant literature, local and national treatment guidelines, and package labeling for further guidance.