Oxazolidinones and Human Immunodeficiency Virus

Abstract

We would like to comment on the potential implications of the article published by McKee et al. (5) on the management of human immunodeficiency virus (HIV)-infected patients. McKee et al. demonstrated that linezolid (and other oxazolidinones) inhibits mitochondrial protein synthesis in rodents (5), confirming similar results in other animal models (4, 6) and in case reports of three humans exposed to linezolid, in which the spectrophotometric determination of enzyme activity for mitochondrial respiratory-chain complex IV in mononuclear cells was found to be low (7). The consequences of this mitochondrial toxicity may include bone marrow suppression, peripheral and optical neuropathy, and lactic acidosis. A recent report from the XVI International AIDS Conference showed a significant increase in the incidence of community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) infections among HIV patients (2). The authors concluded that HIV-infected patients had an 18-fold-higher risk of acquiring CA-MRSA than non-HIV-infected patients. Although the initial therapy for CA-MRSA infection is usually a tetracycline or trimethoprim-sulfamethoxazole (plus appropriate debridement), linezolid is commonly used in more severe CA-MRSA infections. Although no reports of enhanced toxicity have been published, we foresee a potential risk with the concurrent use of linezolid and antiretroviral therapy. Nucleoside reverse transcriptase inhibitors (NRTIs), which are the cornerstone of current antiretroviral combinations, also have the potential for inhibiting mitochondrial DNA. The toxicity can occur with any member of the pharmacological class, although lamivudine and newer NRTIs such as emtricitabine, tenofovir, and abacavir have less toxicity than zalcitabine, stavudine, or didanosine (8). Mitochondrial toxicity related to NRTIs manifests as myopathy, peripheral neuropathy, and lactic acidosis but may also be associated with metabolic disorders including lipoatrophy, insulin resistance, and dyslipidemia. We suggest caution with the concurrent use of oxazolidinones and NRTIs, particularly if the former are planned for long courses of therapy. Clinicians may also want to avoid the additional use of other drugs that may worsen mitochondrial dysfunction. Metformin, which is becoming more commonly used among HIV-infected patients as a consequence of insulin resistance, is a mild inhibitor of respiratory chain complex 1 (3). Ethambutol, a first-line agent in the treatment of tuberculosis, probably causes optic neuropathy by inducing mitochondrial damage (1). If evidence of adverse interactions between oxazolidinones and NRTIs becomes available, additional research into this potential toxicity should be encouraged.