The pharmacokinetics of mecillinam and pivmecillinam in pregnant and non-pregnant women.

1. The pharmacokinetics of parenteral mecillinam (n = 27) and oral pivmecillinam (n = 12) were studied in pregnant (n = 27) and non-pregnant (n = 12) subjects. 2. In early pregnancy (9-14 weeks of gestation) the mean peak plasma drug concentration (Cmax = 19 +/- 9 micrograms ml-1) after an intravenous injection of 200 mg mecillinam was significantly lower (P less than 0.05) and the volume of distribution (V = 49 +/- 20.1) significantly larger (P less than 0.05) than in non-pregnant subjects (Cmax = 35 +/- 18 micrograms ml-1, V = 29 +/- 12.1). In late pregnancy (39-40 weeks of gestation) the plasma mean peak concentration (Cmax = (29 +/- 14 micrograms ml-1) after parenteral administration of 200 mg mecillinam was slightly lower and the volume of distribution (V = 65 +/- 29.1, V = 0.9 +/- 0.4 l kg-1) significantly larger than that in non-pregnant subjects (V = 0.4 +/- 0.3 l kg-1). Also after oral administration of 200 mg pivmecillinam, equimolar to 136.5 mg mecillinam, the mean peak plasma concentration in pregnant subjects (Cmax = 1.8 +/- 1.2 micrograms ml-1) was slightly lower than that in non-pregnant subjects (Cmax = 1.7 +/- 1.2 micrograms ml-1). 3. The mean half-life of elimination after parenteral administration of mecillinam was significantly longer during both early (t1/2,Z = 133 +/- 38 min, P less than 0.05) and late pregnancy (t1/2,Z = 107 +/- 41 min, P less than 0.05) as compared with the non-pregnant state (t1/2,Z = 75 +/- 21 min).(ABSTRACT TRUNCATED AT 250 WORDS)

Bacterial epididymitis in the rat: a model for assessing the impact of acute inflammation on epididymal antibiotic penetration.

A rat model of bacterial epididymitis was developed and characterized for use in assessing the impact of acute epididymal inflammation on antibiotic penetration into the epididymis. A 0.2 ml. intratesticular injection of a 0.5 McFarland standard suspension of E. coli resulted in histologically confirmed acute epididymitis in all animals studied. Inflammatory changes were detectable as early as 24 hours following inoculation and were progressive to the last assessment point at 11 days. Early testicular infarction was observed in association with epididymal inflammation. Serial transcrotal ultrasounds of infected animals showed progressive increase in epididymal size and a late decrease in testicular size. Serum and epididymal drug concentrations were assayed following a single dose of the antibiotic amdinocillin. Fifteen minutes following the peak serum level, the drug concentration in infected epididymis was 2.3-fold higher than the contralateral, non-infected epididymis. These data suggest that acute inflammation enhances antibiotic penetration into the infected epididymis. The model described provides a rapid, reproducible method to study epididymal drug delivery in normal and diseased states.

Influence of food on bioavailability of amdinocillin pivoxil.

The bioavailability of amdinocillin was not altered when amdinocillin pivoxil was ingested 1 h before a standard breakfast, and it increased by 20% when amdinocillin pivoxil was ingested with or 1 h after a standard breakfast. Amdinocillin pivoxil would be convenient for patients since it may be taken with or without food.

The influence of renal functional changes on the intrarenal distribution and urinary kinetics of amdinocillin.

The maintenance of effective therapeutic concentrations of antibiotics within the renal parenchyma is an important issue in the management of acute and chronic pyelonephritis. Available clinical data indicate that an important clinical-therapeutic correlation exists between the physiologic state of the kidney and the antibiotic concentrations that can be achieved in the medulla and papilla. Using a healthy canine model, we evaluated the influence of hydration and the state of acid-base balance upon the intrarenal distribution and urinary clearance of the semisynthetic penicillin amdinocillin. Renal physiologic activity significantly modulates the intrarenal distribution pattern of this compound. During the production of maximally acid and concentrated urine, the highest renal parenchyma levels of amdinocillin are achieved. During the latter circumstances the antibiotic undergoes distal tubular nonionic diffusion, which appears to be an important contributing factor to the high medullary and papillary concentrations of the drug. Nonetheless, at all levels of tested renal physiologic activity tissue and urine drug concentrations are adequate for the treatment of sensitive urinary pathogens.

Factors influencing the absorption and disposition of mecillinam and pivmecillinam in man.

In a pharmacokinetic study in six volunteers peak serum mecillinam concentrations were proportional to the oral dose of pivmecillinam at two dose levels of 200 and 400 mg. Effects of bed rest, probenecid and a 6 day course of treatment with pivmecillinam on serum mecillinam concentrations after an oral dose of pivmecillinam (two 200 mg capsules) have been investigated. Resting subjects had lower peak serum levels and a decreased rate of clearance than moderately active subjects, changes which are similar to those previously reported for benzylpenicillin. Pretreatment with probenecid produced significantly higher serum mecillinam levels, a longer serum antibiotic half-life and a decreased rate of drug clearance which suggests that mecillinam is actively excreted by kidney tubules. Plasma mecillinam level profiles obtained after the first dose of a 6 day treatment period were not significantly different from corresponding values after the first dose on the seventh day which indicates that each dose of mecillinam is eliminated in healthy young adults before succeeding doses are taken.