Carbamazepine toxicity induced by lopinavir/ritonavir and nelfinavir.

OBJECTIVE: To present a case of carbamazepine toxicity induced by lopinavir/ritonavir and nelfinavir. CASE SUMMARY: A 50-year-old HIV-positive male developed excessive drowsiness secondary to carbamazepine when an antiretroviral regimen containing lopinavir/ritonavir was introduced. The carbamazepine serum concentration increased 46%. Subsequently, the patient developed a possible adverse skin reaction to his antiretrovirals and was hospitalized. The protease inhibitor was changed to nelfinavir. Within 3 days, the patient again developed excessive drowsiness and became unsteady on his feet. This time, the carbamazepine serum concentration had increased by 53%. In both instances, the carbamazepine dosage was decreased by 33%, which resulted in resolution of symptoms. DISCUSSION: Carbamazepine undergoes extensive hepatic metabolism. The major metabolic pathway involves oxidation of carbamazepine via CYP3A4 to an active metabolite, carbamazepine-10,11-epoxide. Protease inhibitors are well-known CYP3A4 inhibitors. Other cases of carbamazepine toxicity secondary to protease inhibitors are reviewed. A MEDLINE search (1966-May 2006) revealed 4 cases of carbamazepine toxicity secondary to antiretrovirals. Carbamazepine serum concentrations increased two- to threefold from baseline. Vertigo, drowsiness, disorientation, ataxia, and vomiting occurred within 12 hours to 2 months, which resolved with reduction of the carbamazepine dosage. CONCLUSIONS: An objective causality assessment suggests that our patient became drowsy and unsteady on his feet secondary to a carbamazepine-protease inhibitor interaction. Lopinavir/ritonavir and nelfinavir may decrease carbamazepine metabolism, causing an elevation in carbamazepine serum concentrations. Carbamazepine toxicity may be prevented by reducing the carbamazepine dosage by 25-50% when protease inhibitors are introduced. A carbamazepine serum concentration should be repeated 3-5 days after the protease inhibitors are started.

Aminoglycoside ototoxicity.

Over the last 10 years new information has been published providing a better understanding of the risk factors, mechanism and prevention of aminoglycoside ototoxicity. The use of a higher dose and once-daily intravenous administration of aminoglycosides has shown clinical effectiveness with no increase in ototoxicity when compared to traditional regimens. An enhanced susceptibility to aminoglycoside cochlear toxicity has been linked to an A-to-G substitution in location 1555 of the mitochondrial ribosomal ribonucleic acid (RNA). More recently, a second mutation involving a thymidine deletion in the 12s ribosomal RNA gene has been identified which can predispose patients to aminoglycoside auditory toxicity. Experimental evidence in animals has indicated that reactive oxygen species are one of the most important factors responsible for the development of aminoglycoside ototoxicity. The animal data has suggested a decrease in hearing loss induced by aminoglycosides when antioxidant or iron chelator therapy is given concomitantly with aminoglycoside antibiotics.

Ototoxicity induced by gentamicin and furosemide.

OBJECTIVE: To present a case of ototoxicity induced by furosemide and once-daily gentamicin therapy. CASE SUMMARY: A 60-year-old white woman presented to the hospital with community-acquired pneumonia and urinary tract infection. The antibiotic regimen included gentamicin and, after 5 doses, the patient reported profound bilateral hearing loss. A Pure Tone Audiogram suggested moderate to moderately severe sensorineural hearing loss bilaterally. The only risk factors present included her age, elevated temperature, and the use of furosemide. DISCUSSION: Several risk factors may predispose a patient to developing aminoglycoside ototoxicity: the 1555 chromosomal mutation, preexisting disorders of hearing and balance, hypovolemia, bacteremia, liver and renal dysfunction, and the simultaneous administration of other ototoxic medications. The cumulative dose and duration of aminoglycoside therapy are more important than serum concentrations. Administration of an aminoglycoside followed by furosemide may increase the risk of ototoxicity. The aminoglycoside interacts with the cell membranes in the inner ear, increasing their permeability. This theoretically allows the loop diuretic to penetrate into the cells in higher concentrations, causing more severe damage. CONCLUSIONS: Auditory toxicity occurred after only 5 days of gentamicin therapy and 1 dose of furosemide. An aminoglycoside followed by furosemide may increase the risk for ototoxicity. Clinicians need to be aware of the synergistic potential of ototoxic medications.