A sequence symmetry analysis of the interrelationships between statins, diabetes and skin infections.

AIMS: To determine statins' impact on skin infection risk in view of conflicting literature: that statins may reduce infection risk, but are also associated with diabetes mellitus, a risk factor for skin and soft tissue infections (SSTIs). METHODS: Sequence symmetry analysis was performed on prescription claims (2001-2011) from the Australian Department of Veterans' Affairs to determine the interrelationships between: (i) statins and SSTIs; (ii) statins and diabetes; and (iii) diabetes and SSTIs; as well as whether statins increased the risk of SSTIs, independent of diabetes status. Chi-square tests were performed to detect differences in Index of Relative Socio-economic Advantage and Disadvantage scores of patients within each interrelationship. Prescriptions for statins, antidiabetic medication, and antistaphylococcal antibiotics were evaluated using nonidentifiable client numbers, prescription dates filled, residential electorates, and pharmaceutical codes. Adjusted sequence ratio and confidence interval were calculated at intervals of 91, 182 and 365 days for sequence symmetry analysis studies. RESULTS: Statins were associated with: (i) significant SSTI risk (adjusted sequence ratio > 1; confidence interval >1), (ii) significant diabetes risk, and (iii) diabetic patients had increased risk of SSTIs. Diabetic and nondiabetic statin users had significantly increased risks of SSTIs, while the influence from socioeconomic status was not significant for each of the 3 relationships. CONCLUSIONS: Statins are associated with increased risk of SSTIs via direct and indirect mechanisms, probably independent of diabetes or socioeconomic statuses. We believe that clinicians should be aware of the association between statins and SSTIs, and, where appropriate, monitor blood glucose levels of statin users.

In vitro antibacterial effects of statins against bacterial pathogens causing skin infections.

With financial considerations impeding research and development of new antibiotics, drug repurposing (finding new indications for old drugs) emerges as a feasible alternative. Statins are extensively prescribed around the world to lower cholesterol, but they also possess inherent antimicrobial properties. This study identifies statins with the greatest potential to be repurposed as topical antibiotics and postulates a mechanism of action for statins' antibacterial activity. Using broth microdilution, the direct antibacterial effects of all seven parent statins currently registered for human use and three selected statin metabolites were tested against bacterial skin pathogens Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, and Serratia marcescens. Simvastatin and pitavastatin lactone exerted the greatest antibacterial effects (minimum inhibitory concentrations of 64 and 128 µg/mL, respectively) against S. aureus. None of the statins tested were effective against E. coli, P. aeruginosa, or S. marcescens, but simvastatin hydroxy acid acid might be active against S. aureus, E. coli, and S. marcescens at drug concentrations > 256 µg/mL. It was found that S. aureus may exhibit a paradoxical growth effect when exposed to simvastatin; thus, treatment failure at high drug concentrations is theoretically probable. Through structure-activity relationship analysis, we postulate that statins' antibacterial action may involve disrupting the teichoic acid structures or decreasing the number of alanine residues present on Gram-positive bacterial cell surfaces, which could reduce biofilm formation, diminish bacterial adhesion to environmental surfaces, or impede S. aureus cell division.

Statins: antimicrobial resistance breakers or makers?

INTRODUCTION: The repurposing of non-antibiotic drugs as adjuvant antibiotics may help break antimicrobial resistance (AMR). Statins are commonly prescribed worldwide to lower cholesterol. They also possess qualities of AMR "breakers", namely direct antibacterial activity, synergism with antibiotics, and ability to stimulate the host immune system. However, statins' role as AMR breakers may be limited. Their current extensive use for cardiovascular protection might result in selective pressures for resistance, ironically causing statins to be AMR "makers" instead. This review examines statins' potential as AMR breakers, probable AMR makers, and identifies knowledge gaps in a statin-bacteria-human-environment continuum. The most suitable statin for repurposing is identified, and a mechanism of antibacterial action is postulated based on structure-activity relationship analysis. METHODS: A literature search using keywords "statin" or "statins" combined with "minimum inhibitory concentration" (MIC) was performed in six databases on 7th April 2017. After screening 793 abstracts, 16 relevant studies were identified. Unrelated studies on drug interactions; antifungal or antiviral properties of statins; and antibacterial properties of mevastatin, cerivastatin, antibiotics, or natural products were excluded. Studies involving only statins currently registered for human use were included. RESULTS: Against Gram-positive bacteria, simvastatin generally exerted the greatest antibacterial activity (lowest MIC) compared to atorvastatin, rosuvastatin, and fluvastatin. Against Gram-negative bacteria, atorvastatin generally exhibited similar or slightly better activity compared to simvastatin, but both were more potent than rosuvastatin and fluvastatin. DISCUSSION: Statins may serve as AMR breakers by working synergistically with existing topical antibiotics, attenuating virulence factors, boosting human immunity, or aiding in wound healing. It is probable that statins' mechanism of antibacterial activity involves interference of bacterial cell regulatory functions via binding and disrupting cell surface structures such as wall teichoic acids, lipoteichoic acids, lipopolysaccharides, and/or surface proteins. The widespread use of statins for cardiovascular protection may favor selective pressures or co-selection for resistance, including dysbiosis of the human gut microbiota, sublethal plasma concentrations in bacteremic patients, and statin persistence in the environment, all possibly culminating in AMR. CONCLUSION: Simvastatin appears to be the most suitable statin for repurposing as a novel adjuvant antibiotic. Current evidence better supports statins as potential AMR breakers, but their role as plausible AMR makers cannot be excluded. Elucidating the mechanism of statins' antibacterial activity is perhaps the most important knowledge gap to address as this will likely clarify statins' role as AMR breakers or makers.