Antibiotic prophylaxis for the prevention of infective endocarditis for dental procedures is not associated with fatal adverse drug reactions in France

Background: One of the major reasons to stop antibiotic prophylaxis (AP) to prevent infective endocarditis (IE) in the United Kingdom but not in the rest of the world was that it would result in more deaths from fatal adverse drug reactions (ADRs) than the number of IE deaths. The main aim of this study was to quantify and describe the ADRs with amoxicillin or clindamycin for IE AP. The second aim was to infer a crude incidence of anaphylaxis associated with amoxicillin for IE AP. Study design: The Medical Dictionary for Regulatory Activities (MedDRA) was used to group ADRs for IE AP using the broad Standardized MedDRA Queries "Anaphylactic reaction, Amoxicillin, Clindamycin, Clostridium Difficile infection" to the French Pharmacovigilance Database System. From this first-line collection, we selected all cases occurring for IE AP and ultimately, the cases for IE AP for a dental procedure. Then, each case was analyzed. Results: Of 11639 first-line recorded ADRs, 100 were for IE AP but no fatal anaphylaxis to amoxicillin or clindamycin and no C. difficile infection associated with clindamycin were identified. Only 17 cases of anaphylaxis to amoxicillin related to dental procedures were highlighted. The estimation of the crude incidence rate of anaphylaxis associated with amoxicillin for IE AP for invasive dental procedure was 1/57 000 (95% CI 0.2-0.6). Conclusions: Fatal or severe ADRs with amoxicillin or clindamycin is not a rational argument to stop IE AP before invasive dental procedures

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Rapid control of severe neoplastic hypercortisolism with metyrapone and ketoconazole.

CONTEXT: Severe Cushing's syndrome elicited by ectopic ACTH syndrome (EAS) or adrenal carcinoma (ACC) can threaten life in the short term. The effectiveness of oral administration of the inhibitors of steroidogenesis ketoconazole and metyrapone in this situation is poorly described. OBJECTIVE: To report the short-term effectiveness and tolerability of metyrapone and ketoconazole elicited either by EAS or by ACC in patients exhibiting severe hypercortisolism. DESIGN: Retrospective analysis of data obtained for patients with urinary free cortisol (UFC) level estimated to be fivefold the upper limit of the normal range (ULN). PATIENTS AND SETTINGS: A total of 14 patients with EAS and eight with ACC treated in two tertiary-care university hospitals. INTERVENTION: Metyrapone and ketoconazole treatment in combination (along with symptomatic treatments for co-morbidities). MAIN OUTCOME: Evolution of clinically relevant endpoints (blood pressure, kalaemia and glycaemia) and biological intensity of hypercortisolism 1 week and 1 month after starting steroidogenesis inhibition. RESULTS: After 1 week of treatment, median UFC fell from 40.0 to 3.2 ULN and from 16.0 to 1.0 ULN in patients with EAS and ACC respectively. Median UFC after 1 month of treatment was 0.5 and 1.0 ULN in patients with EAS and ACC respectively and UFC values were normal in 73 and 86% of patients respectively. Clinical status improved dramatically along with kalaemia, glycaemia and blood pressure, allowing a decrease in the relevant treatments.Side effects were minimal and only two patients (one EAS and one ACC) experienced plasma transaminase elevations necessitating ketoconazole withdrawal. CONCLUSION: Metyrapone-ketoconazole combination therapy is well tolerated and provides rapid control of endocrine cancer-related life-threatening hypercortisolism.

Ketoconazole in Cushing's disease: is it worth a try?

BACKGROUND: The use of ketoconazole has been recently questioned after warnings from the European Medicine Agencies and the Food and Drug Administration due to potential hepatotoxicity. However, ketoconazole is frequently used as a drug to lower circulating cortisol levels. Several pharmacological agents have recently been approved for the treatment of Cushing's disease (CD) despite limited efficacy or significant side effects. Ketoconazole has been used worldwide for more than 30 years in CD, but in the absence of a large-scale study, its efficacy and tolerance are still under debate. PATIENTS AND METHODS: We conducted a French retrospective multicenter study reviewing data from patients treated by ketoconazole as a single agent for CD, with the aim of clarifying efficacy and tolerance to better determine the benefit/risk balance. RESULTS: Data from 200 patients were included in this study. At the last follow-up, 49.3% of patients had normal urinary free cortisol (UFC) levels, 25.6% had at least a 50% decrease, and 25.4% had unchanged UFC levels. The median final dose of ketoconazole was 600 mg/d. Forty patients (20%) received ketoconazole as a presurgical treatment; 40% to 50% of these patients showed improvement of hypertension, hypokalemia, and diabetes, and 48.7% had normal UFC before surgery. Overall, 41 patients (20.5%) stopped the treatment due to poor tolerance. Mild (<5N, inferior to 5-fold normal values) and major (>5N, superior to 5-fold normal values) increases in liver enzymes were observed in 13.5% and 2.5% of patients, respectively. No fatal hepatitis was observed. CONCLUSIONS: Ketoconazole is an effective drug with acceptable side effects. It should be used under close liver enzyme monitoring. Hepatotoxicity is usually mild and resolves after drug withdrawal.