Imipenem pharmacokinetics and body fluid concentrations in patients receiving high-dose treatment for serious infections

Abstract

Serum, urine, tissue, and body fluids were collected from 40 adult patients who were receiving imipenem/cilastatin treatment for serious infections. Thirty-two patients were given 1 g every 6 h (4 g/day), and eight received 500 mg (2 g/day). Mean peak concentrations in serum were 34.9 ± 4.0 p.g/ml for the 1-g dose and 26.6 ± 2.5 ,ug/ml for the 500-mg dose. Trough levels were 3.1 and 1.0 ,ug/ml, respectively. Imipenem (formerly N-formimidoyl thienamycin [MK0787]) is a stabilized amidine derivative of thienamycin, the first member of a new class of beta-lactam antibiotics, the carbapenems, which are characterized by their possession of a desthiocarbapenem nucleus (6,8). The combination of impressive activity against most aerobic and anaerobic bacterial species (9, 15) and the relatively low incidence of toxic reactions that is typical for the beta-lactam antibiotics as a group (5) Most patients received a dosage of 1 g of imipenem combined with 1 g of cilastatin intravenously every 6 h, although late in the trial some were given 500 mg of each to conserve the drug. Unless otherwise noted, data presented below are from those patients who received the higher dose. A 1-g amount of imipenem/cilastatin was dissolved in either 200 ml of isotonic saline or 5% dextrose in water and infused over 30 to 60 min. Because of the large volume, most infusions required 60 min.Plasma was obtained 15 min after the end of the infusion (peak) and 5 h later, immediately before the next dose (trough). A 15-min postinfusion time was chosen to allow for the distribution phase of the drug. Norrby et al. (12) showed that the half-life at alpha phase (t112,) equaled 10 min for a 250-mg dose administered intravenously over 5 min. Therefore, when the drug was administered over 1 h, a 15-min period was deemed adequate for distribution after end infusion. Twenty-six patients had an additional midpoint specimen obtained between 2 and 3 h after the end of the infusion for the construction of an antibiotic plasma half-life (t012) curve. Blood was drawn into heparinized tubes, iced immediately, and transported to the laboratory within 1 h, where it was centrifuged at 4°C, and the plasma was mixed 1:1 with a stabilizing buffer containing equal volumes of 1 M morpholinoethane sulfonate and ethylene glycol. Then it was stored at -70°C until being shipped on dry ice to the Merck Institute for assay.In 25 patients, urine was collected for 6 h, beginning with the start of one infusion and ending with the start of the next. All specimens were iced on voiding and, at the end of the collection period, brought promptly to the laboratory and processed in the same way as the plasma specimens. Urine creatinine concentration and 6-h creatinine clearance (CLCR) were determined to verify the adequacy of the collection and to compare imipenem excretion with CLCR rates.

Pharmacokinetics and transplacental passage of imipenem during pregnancy

“…The pharmacokinetic characteristics for the nonpregnant women correspond well to those reported previously (13). During pregnancy, however, many of the observed parameters differ significantly from those in the nonpregnant state.…”

Pharmacokinetics and Pharmacodynamics of Imipenem during Continuous Renal Replacement Therapy in Critically Ill Patients

“…Increased proportions of imipenem clearance due to nonrenal mechanisms have been previously reported in anuric patients and patients receiving CRRT (25,38,43), as well as for other antimicrobials in patients with severe renal insufficiency (16,23). Although critically ill patients with severe acute renal failure are typically fluid overloaded, no apparent increase in the V of imipenem was noted in this study compared to that previously described in healthy volunteers and patients with renal insufficiency (14,15,22,43). This may perhaps be explained by the fact that subjects in this study had already received at least 24 to 48 h of CRRT with removal of a large fluid volume prior to measurement of imipenem concentrations.…”

Biliary excretion of imipenem-cilastatin in hospitalized patients

“…This calculation corresponds closely with the finding by Norrby et al that less than 2% of the radiolabeled, intravenously administered drug was recovered from the stool (10). When this lack of bile and gastrointestinal excretion of imipenem is combined with evidence that only 60 to 70% of imipenem is recovered unchanged from the urine (7,9), it is clear that an additional mechanism(s) for the elimination of this drug must exist.…”

“…It was thought that it might not cause diarrhea because Norrby et al (10) found that less than 2% bf the radiolabeled, intravenously administered drug,could be recovered in the stool and because Nord and his colleagues (8) detected only minor changes in bowel flora after 6 to 11 days of its use. However, the review by Calandra et al (2) of adverse experiences among the first 2,516 patients treated with imipenem-cilastatin reported a 3.3% incidence of diarrhea, including several cases in which Clostridium difficile toxin was isolated (3,7,16). In an earlier report, we demonstrated concentrations of imipenem in various gastrointestinal fluids that were high enough to inhibit' most intestinal flora (7).…”

“…However, the review by Calandra et al (2) of adverse experiences among the first 2,516 patients treated with imipenem-cilastatin reported a 3.3% incidence of diarrhea, including several cases in which Clostridium difficile toxin was isolated (3,7,16). In an earlier report, we demonstrated concentrations of imipenem in various gastrointestinal fluids that were high enough to inhibit' most intestinal flora (7). The current study was undertaken to determine the degree to which imipenem and cilastatin entered the gastrointestinal tract through biliary excretion.…”