The chemotherapeutic drug methotrexate selects for antibiotic resistance

Understanding drivers of antibiotic resistance evolution is fundamental for designing optimal treatment strategies and interventions to reduce the spread of antibiotic resistance. Various cytotoxic drugs used in cancer chemotherapy have antibacterial properties, but how bacterial populations are affected by these selective pressures is unknown. Here we test the hypothesis that the widely used cytotoxic drug methotrexate affects the evolution and selection of antibiotic resistance through the same mechanisms as the antibiotic trimethoprim. We show that methotrexate can select for trimethoprim resistance determinants located on the chromosome or a plasmid in clinical strains of Escherichia coli. Additionally, methotrexate can co-select for virtually any antibiotic resistance determinant when present together with trimethoprim resistance on a multidrug-resistance clinical plasmid. These selective effects occur at concentrations 40- to >320-fold below the methotrexate minimal inhibitory concentration for E. coli, suggesting a selective role of methotrexate chemotherapy for antibiotic resistance in patients that strongly depend on effective antibiotic treatment.

ML-04 The influence of surgical intervention for high-dose Methotrexate chemotherapy in the patients with primary central nervous system lymphoma

Object: Surgical resection is not the standard of treatment for primary central nervous system lymphoma (PCNSL). Some recent studies suggest that resection might be beneficial. The aim of this study was to examine the effect of surgical treatment in terms of the time from surgery to chemotherapy. Methods: We retrospectively analyzed all patients with PCNSL treated at Hokkaido University Hospital between 2001 and 2018 to assess the effect of selection for resection on the response of Methotrexate chemotherapy. We identified the days from surgery to chemotherapy, complications, the response of Methotrexate (CR/CRu rate) and prognostic factors including progression free survival (PFS) and overall survival (OS). Results: A total 105 patients were identified. 84 patients underwent biopsy and 21 patients underwent surgical resection. Their median age were 63 [31–78] and 68 [44–77], respectively. Their Karnofsky Performance Status (KPS) were 70 [30–100] and 70 [40–100]. There were any significant difference. Patients undergoing biopsy and those undergoing resection had comparable rates of complications for all complication type. Overall, 4 biopsy patients and 5 resection patients experienced at least one complication. They were composed of 2 asymptomatic bleeding, 1 wound abscess, 1 hydrocephalus in biopsy patients, 1 epidural abscess, 1 epilepsy, 1 chronic subdural hematoma, 2 temporary hemiparesis. Although the days from surgery to chemotherapy were significantly shorter in patients underwent biopsy than in those underwent resection (P=0.0015), PFS was significantly longer in patients underwent resection than in those underwent biopsy (P=0.0403), whereas there was no difference in OS. Discussion: Resection could delay the postoperative treatment. In this study, there was a significant delay of postoperative treatment in resection patients, however, CR/CRu rate after MTX was significantly better in those underwent resection than biopsy. We can see that resection for PCNSL might not necessarily worsen the prognosis.