Patients with Obesity Should be Recognised as a Special Patient Population During Drug Development of Antibacterial and Antifungal Agents; A Call to Action.

Individuals with obesity are at increased risk of developing infectious diseases. Timely administration of an effective dose of an antimicrobial agent is paramount to safeguard optimal therapy. For this purpose, special patient populations at risk for altered exposure such as renal or hepatic impairment are studied during drug development. Strikingly, there is no such evaluation in individuals with obesity despite a potential influence on exposure and a global obesity prevalence of 13 %. Optimal clinical decision making in patients with obesity is impossible without prior study of the drug of interest in this population. This statement is strengthened by an evaluation of 19 antimicrobial agents that showed tremendous variability in the influence of weight on clearance. In contrast to patient with renal or hepatic impairment who are mainly at risk of overexposure, individuals with obesity can be at risk of both under- and overexposure. Gaining knowledge on the influence of body weight on clearance during early phases of drug development may allow for optimisation of other phases of research, potentially increasing success rate of the drug, and can provide clinicians with vital information as soon as the drug reaches the market. Antimicrobial therapy should be tailored to obesity-related (patho)physiological changes and to reach this goal, obese individuals should be studied during drug development.

Impact of mucositis on oral bioavailability and systemic exposure of ciprofloxacin Gram-negative infection prophylaxis in patients with haematological malignancies.

BACKGROUND: Patients with haematological malignancies frequently endure neutropenia and gastrointestinal (GI)-mucositis after high-dose chemotherapy. In these patients, ciprofloxacin is used for Gram-negative infection prophylaxis. OBJECTIVES: We investigate ciprofloxacin pharmacokinetics after oral administration in patients with haematological malignancies and explore the impact of GI-mucositis on oral bioavailability and clearance in order to assure adequate systemic exposure. METHODS: Adult haematological patients from two Dutch University Medical Centres received 500 mg twice daily oral ciprofloxacin for Gram-negative prophylaxis. The ciprofloxacin plasma concentrations were collected at various timepoints after oral ciprofloxacin administration and at various days after completion of chemotherapy. Data obtained after oral and intravenous ciprofloxacin administration in 28 healthy volunteers without mucositis served as a control group (391 samples). For haematological patients the degree of GI-mucositis was assessed using the Daily Gut Score (DGS), plasma citrulline and albumin. Data were analysed by non-linear mixed-effects modelling. RESULTS: In total, 250 blood samples were collected in 47 patients with a wide variety of haematological malignancies between 0-30 days after start of chemotherapy. Mucositis was generally mild [DGS median (IQR) 1 (1-1) and citrulline 16 µmol/L (12-23)]. The time to Cmax was slower in haematological patients compared with healthy volunteers although no association with the degree of mucositis (defined as DGS or citrulline) could be identified. Ciprofloxacin bioavailability and clearance were 60% and 33.2 L/h, respectively. CONCLUSIONS: This study supports oral dosing of ciprofloxacin as Gram-negative infection prophylaxis in haematological patients with mild-to-moderate mucositis capable of oral intake.

[A patient with severe digoxin toxicity]. / Een patiënt met ernstige digoxine-intoxicatie.

BACKGROUND: Digoxin is a cardiac glycoside that is frequently prescribed in atrial fibrillation and heart failure. Symptoms such as nausea, hyperkalaemia, cardiac arrhythmias and cardiac arrest are seen in digoxin toxicity. The treatment focuses on reduction of digoxin absorption, prevention of hypokalaemia and hyperkalaemia, treatment of symptoms and, in severe toxicity, administration of digoxin antibodies. CASE DESCRIPTION: A 73-year-old man with a history of extensive cardiac disease was seen 45 minutes after ingesting 20 mg of digoxin. The patient developed ventricular fibrillation within 3 hours of ingestion, before arrival of the digoxin antibodies. The patient passed away despite resuscitation and administration of an insufficient amount of digoxin antibodies. CONCLUSION: The national supply of digoxin antibodies in the Netherlands proved to be too limited for the treatment of a patient with severe digoxin toxicity. An increase in the supply, and central storage, of digoxin antibodies could promote faster administration of an adequate amount of the antibodies. Timely transportation to an extra corporeal membrane oxygenation centre should also be considered.