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Sodium Fusidate Inhibits rCYP3A4 in vitro-A Possible Mechanism Defining the Interaction with Statins

Daniel Guidone,Robel Getachew,Narin Osman,Michael Ward,Vincent Chan,Peter J Little*

Sodium fusidate (fusidic acid) is an antimicrobial agent used to treat methicillin-resistant Staphylococcus aureus infections. Several case reports have described drug interactions between sodium fusidate and CYP3A4 metabolised statins, leading to statin myotoxicity, including fatal myotoxicity. The mechanism of this interaction is unknown. We investigated the effects of sodium fusidate on recombinant CYP3A4 in vitro and found it to be a timedependent inhibitor of this enzyme at concentrations likely to be achieved with clinical dosing regimens. This finding may help to explain the mechanism of the apparent statin-fusidate interaction. Introduction Sodium fusidate (fusidic acid) is a naturally occurring antibiotic derived from the fungus Fusidium coccineum. It has a narrow antimicrobial spectrum, exhibiting particular activity against Staphylococcus aureus [1]. Sodium fusidate exhibits its primarily bacteriostatic action by inhibition of elongation factor G at a bacterial ribosomal level, which in turn inhibits protein synthesis [2]. As this mode of action is unrelated to that of beta lactams, sodium fusidate retains activity against methicillin-resistant Staphylococcus aureus (MRSA)[3]. Increasing rates of MRSA infection has led to renewed interest in and usage of sodium fusidate [4]. Cardiovascular diseases are the leading cause of disability and death in the world [5]. Hydroxylmethyl glutaryl coenzyme A reductase inhibitors (statins) are established therapies in primary and secondary prevention of cardiovascular disease [6,7]. Consequently, the use of statins has increased worldwide over the last two decades, for example, statin use (measured in defined daily doses per 1000 population per day) increased in Europe by 35 per cent annually over the period 1997 to 2003 [8].Usage in Australia was even higher during this period [9]. Statins are generally well tolerated, although some toxicity is associated with their use. Significant concentration-dependent adverse effects with potentially lethal consequences include muscle toxicity (such as rhabdomyolysis) and hepatotoxicity [10,11]. As these adverse effects are concentration-dependent they may be potentiated by drugdrug interactions which lead to decreased statin clearance. Cytochrome P450 3A4 (CYP3A4) is an important enzyme in the elimination of numerous statins, including atorvastatin and simvastatin, and inhibition of this enzyme is known to increase the likelihood and significance of statin toxicity [11]. Sodium fusidate and statins may be co-prescribed for commonly occurring co-conditions. One example is diabetic foot infection. MRSA is an important pathogen in diabetic foot infection and worsens the outcome of this infection, compared with infections with methicillin-sensitive