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Published on: January 2, 2018
Evaluation of Daptomycin-Induced Cellular Membrane Injury in Skeletal Muscle
Takehiro Yamada1,2, Shuhei Ishikawa1, Nobuhisa Ishiguro2
1Department of Pharmacy, Hokkaido University Hospital.
Abstract:
Daptomycin, a cyclic lipopeptide antibiotic, has bactericidal activity against Gram-positive organisms and is especially effective against methicillin-resistant Staphylococcus aureus. Although daptomycin causes unique adverse drug reactions such as elevation of creatine phosphokinase or rhabdomyolysis, the detailed mechanisms underlying these adverse drug reactions in skeletal muscle are unclear. This study aimed to elucidate whether daptomycin causes direct skeletal muscle cell toxicity and investigate the relationship between daptomycin exposure and musculoskeletal toxicity. First, we evaluated the relationship between daptomycin exposure and skeletal muscle toxicity. Of the 38 patients who received daptomycin intravenously, an elevation in creatine phosphokinase levels was observed in five. The median plasma trough concentration of daptomycin in patients with elevated creatine phosphokinase levels was significantly higher than that in patients whose creatine phosphokinase levels were within the normal range, suggesting that increased exposure to daptomycin is related to elevation in creatine phosphokinase levels. In an in vitro study using human rhabdomyosarcoma cells, daptomycin reduced cell viability and increased membrane damage. These effects were more marked under hypoxic conditions. A necroptotic pathway seemed to be involved because phosphorylated mixed lineage kinase domain-like protein expression was enhanced following daptomycin exposure, which was significantly enhanced under hypoxic conditions. These findings indicate that daptomycin elicits cytotoxic effects against skeletal muscle cells via the necroptotic pathway, and the extent of toxicity is enhanced under hypoxic conditions.
Insights
Daptomycin can harm skeletal muscle cells, potentially causing elevated creatine phosphokinase. This antibiotic-induced muscle toxicity is linked to higher drug levels and is worsened by low oxygen conditions via necroptosis.
Area of Science:
- Pharmacology
- Cell Biology
- Toxicology
Background:
- Daptomycin is a potent antibiotic against Gram-positive bacteria, including MRSA.
- Adverse effects like elevated creatine phosphokinase and rhabdomyolysis are associated with daptomycin, but the mechanisms are not fully understood.
- Skeletal muscle toxicity is a concern with daptomycin therapy.
Purpose of the Study:
- To investigate if daptomycin directly causes skeletal muscle cell toxicity.
- To explore the relationship between daptomycin exposure levels and musculoskeletal adverse events.
- To elucidate the cellular mechanisms underlying daptomycin-induced muscle toxicity.
Main Methods:
- Clinical analysis of patients receiving daptomycin, correlating plasma trough concentrations with creatine phosphokinase levels.
- In vitro studies using human rhabdomyosarcoma cells to assess daptomycin's cytotoxic effects.
- Investigation of the involvement of the necroptotic pathway through marker analysis (phosphorylated MLKL) under varying oxygen conditions.
Main Results:
- Higher daptomycin plasma trough concentrations were significantly associated with elevated creatine phosphokinase levels in patients.
- In vitro, daptomycin reduced cell viability and increased membrane damage in skeletal muscle cells.
- Daptomycin-induced cell death involved necroptosis, a process exacerbated under hypoxic conditions.
Conclusions:
- Daptomycin exhibits direct cytotoxic effects on skeletal muscle cells.
- The necroptotic pathway mediates daptomycin-induced skeletal muscle toxicity.
- Hypoxia significantly enhances daptomycin's toxicity to skeletal muscle cells, suggesting clinical implications for patients with compromised oxygenation.
