Pharmacokinetic Profile of Meropenem, Administered at 500 Milligrams Every 8 Hours, in Plasma and Cantharidin-Induced Skin Blister Fluid

Abstract

The pharmacokinetic disposition of meropenem, administered at 500 mg every 8 h, in plasma and cantharidin-induced blister fluid is described. Peak meropenem concentrations in blister fluid lagged behind peak meropenem concentrations in plasma, while a lower elimination rate from blister fluid was also noted. The mean penetration of meropenem into blister fluid was 67%. The pharmacokinetic profile of meropenem in blister fluid supports the utility of this dose in the management of skin and soft tissue infections.In the United States, meropenem is Food and Drug Administration approved for intra-abdominal infections and bacterial meningitis (Merrem package insert; AstraZeneca Pharmaceuticals, Wilmington, Del., 2001). However, this agent has also been found effective for lower respiratory tract, skin and soft tissue, gynecologic, and complicated urinary tract infections as well as empirical therapy in the febrile neutropenic patient (2-4, 6, 9, 11). While these clinical findings may be anticipated from its plasma profile, it is the drug concentration at the site of infection that best supports clinical efficacy. In the context of skin and soft tissue infections, evaluation of drug concentrations in blister fluid may best approximate drug exposure at the infection site, since this fluid has been noted to resemble the situation within an infected tissue (1). In this study, we evaluated the steady-state pharmacokinetic profile of meropenem, administered at 500 mg every 8 h, in both blister fluid and plasma.Study design and population. Ten volunteers were enrolled in this multiple-dose, open-label study after approval was granted from the Hartford Hospital Institutional Review Board, and written informed consent was obtained. Volunteers were 21 to 42 years of age (mean age, 26.8 years), weighed between 68 and 118 kg (mean weight, 86.2 kg), and had a mean height of 1.8 m (range, 1.68 to 1.88 m). Volunteers underwent two complete physical exams within 21 days and 48 h before the study and were considered normal. Laboratory evaluations, including blood chemistries, hematology, and urinalysis, revealed no abnormalities.Blister induction and drug administration. Volunteers received intravenous doses of 500 mg of meropenem (lot no. 6199C; AstraZeneca Pharmaceuticals) in 250 ml of normal saline over 30 min every 8 h for a total of three doses. After the first dose, and approximately 14 h before pharmacokinetic sampling, 0.2-ml drops of an ointment containing 0.25% cantharidin made from cantharidin powder (Sigma Laboratories, St. Louis, Mo.) and standard ointment base were applied to the anterior forearms of the volunteers to produce a total of six blisters per volunteer. The integrity of the blisters was maintained by spraying them with a fast-drying plastic dressing (New-Skin Liquid Bandage Spray; Medtech Laboratories, Inc., Jackson, Wyo.). Volunteers were allowed to take food and drink ad libitum. Caffeine intake was not permitted.Pharmacokinetic sampling. Blood samples were collected into heparinized Vacutainers from an ind...

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