Low concentrations of clarithromycin upregulate cellular antioxidant enzymes and phosphorylation of extracellular signal-regulated kinase in human small airway epithelial cells

Abstract Background It is well known that low-dose, long-term macrolide therapy is effective against chronic inflammatory airway diseases. Oxidative stress is considered to be a key pathogenesis factor in those diseases. However, the mechanism of action of low-dose, long-term macrolide therapy remains unclear. We have reported that clarithromycin (CAM), which is a representative macrolide antibiotic, could inhibit hydrogen peroxide (H2O2)-induced reduction of the glutathione (GSH)/glutathione disulfide (GSSG) ratio in human small airway epithelial cells (SAECs), via the maintenance of GSH levels through an effect on γ-glutamylcysteine synthetase (γ-GCS) expression. In this study, we examined the influence of CAM against H2O2-induced activities of cellular antioxidant enzymes and phosphorylated extracellular signal regulatory kinase (p-ERK) using SAECs, the main cells involved in chronic airway inflammatory diseases. Methods SAECs were pretreated with CAM (1, 5, and 10 μM) for 72 h, and subsequently exposed to H2O2 (100 μM) for 0.5–2 h. Levels of GSH and GSSG, and activities of glutathione peroxidase (GPx)-1, glutathione reductase (GR), superoxide dismutase (SOD), catalase (CAT), heme oxygenase (HO)-1 and p-ERK were assayed. mRNA expressions of GPx-1 and HO-1 were measured using the real-time reverse transcription polymerase chain reaction (RT-PCR). Tukey’s multiple comparison test was used for analysis of statistical significance. Results Pretreatment with low-dose (1 and 5 μM) CAM for 72 h inhibited H2O2-induced reductions of GPx-1, GR, SOD, CAT and HO-1 activities, and mRNA expressions of GPx-1 and HO-1, and improved the GSH/GSSG ratio. However, these alterations were not observed after pretreatment with high-dose (10 μM) CAM, which suppressed phosphorylation of cell proliferation-associated ERK to cause a significant (p < 0.01) decrease in cell viability. Conclusions CAM is efficacious against deterioration of cellular antioxidant enzyme activity caused by oxidative stress under low-dose, long-term treatment conditions. On the other hand, pretreatment with high-dose CAM suppressed phosphorylation of cell proliferation-associated ERK and decreased cell viability. The present study may provide additional evidence as to why low-dose, long-term administration of macrolides is effective for treating chronic inflammatory airway diseases

Effect of Different Approaches to Antimicrobial Therapy with Cefmetazole and Meropenem on the Time to Defervescence in Non-Severe Extended-Spectrum β-Lactamase-Producing <i>Escherichia coli</i> Bacteremia

Carbapenems are antimicrobial agents commonly used to treat extended-spectrum β-lactamase (ESBL)-producing bacteria. Although cefmetazole (CMZ) is considered effective for ESBL-producing Escherichia coli (ESBL-EC) bacteremia, previous studies showed its limitations, including the influence of the initial antimicrobial agent. Here, we examined the effects of different approaches to antimicrobial therapy with CMZ and meropenem (MEPM) on the time to defervescence in ESBL-EC bacteremia. Notably, the influence of previous antimicrobial agents was excluded. Inpatients with ESBL-EC detected in blood cultures between April 2018 and March 2023 were included and assigned to CMZ (n = 14), MEPM (n = 8), de-escalation to CMZ (dCMZ; n = 9), or escalation to MEPM (eMEPM; n = 11) groups. The median time to defervescence was 3.5, 1.0, 2.0, and 4.0 days in the CMZ, MEPM, dCMZ, and eMEPM groups, respectively, with no significant differences. Cox proportional hazards analysis showed a significant difference in the hazard ratio (95% confidence interval) of 0.378 (0.145–0.984) for the time to defervescence with CMZ versus MEPM (p = 0.046). The extent of a delayed time to defervescence is greater with early CMZ administration than with MEPM administration in patients with non-severe ESBL-EC bacteremia